M Ignacio

M Roland Liblau

M Herman Waldmann

Ms Nathalie Chaput

Ms Clotilde Thery

Ms Veronique

M Alain Bessis

M Antoine Toubert

M Joël Pestel

M François Lemoine

Ana-Maria Lennon-Duménil

Ms Christine Tuffereau

Ms Evelyne

The site visit took place over one day and a half on February 14th and 15th, 2011. The organization allowed the visit to go smoothly. The visit started by an overall presentation of the structure and scientific goals of the Laboratory by the Director. Then, each team had about one hour to describe their achievements and projects. The committee had enough time to listen to the presentations, discuss their scientific content and to evaluate the research of each of the 6 Teams. Further, the committee had a chance to meet and discuss quite in-depth with each staff category. In addition, discussions with the students around their posters and in a more informal manner could take place. At the end, the review panel met to exchange their views and to organize the preparation of the final report.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The Unit is located over 3000 m2 in the Nantes university hospital in the same building as the Clinical immunology, Nephrology and Urology departments (ITUN). Most core technological platforms, in particular the two animal houses, are in close proximity. Both this Inserm unit and the ITUN have been at the initiation of the Nantes IHU project that, although not among the six most successful projects, has been selected for funding.

The common theme of the unit is the immunology of allo and xeno-transplantation. More specifically, the shared scientific interests revolve around the study of the mechanisms of allograft tolerance, identification of biomarkers associated with allograft acceptance/rejection, the immunological bases of chronic allograft dysfunction, the immunological effectors of kidney diseases leading to transplantation, and xenotransplantation.

 Management team

The unit is directed by Ignacio ANEGON. The Director meets on a weekly basis with the Team leaders and the laboratory manager and the grant manager to deal with managerial, logistics, financial and scientific issues. A formal Laboratory council gathering all the members of the unit meets every 3 months. An international scientific advisory board has been in place for quite some time. It gathers 4 renowned scientists from the USA, UK, Spain and Germany who provide recommandations following a site visit (the last one took place in June 2010). 2  Overall appreciation on the research unit

 Staff members

 Summary

The research unit entitled "Transplantation immunology and immuno intervention" is composed of 6 teams and 11 platforms. Two teams (Team 2 and 5) will be reorganized. Thus, scientists with expertise in hepatology and gene therapy will join Team 2, and Team 5 will be created by merging experts in the field of endothelial cells in transplantation with others having expertise in the immunological bases of kidney diseases. Of note, a new platform on ES and iPS cells will be created soon. Some projects are high ranking; others may appear more risky. The fact that the unit is well managed, dynamic, and well founded provides room for some risk taking.

The overall productivity of the unit is very good, its funding impressive (in a positive way), and its national and international visibity very strong. Taking advantage of their localization on a University Hospital campus, the unit invests strongly in translational biomedical projects and has clear recognition in this field. However, importantly basic projects are also well conducted with some reaching a very good scientific level.

 Strengths and opportunities

-Very strong expertise in the field of transplantation and immune intervention.

-The publication record of the unit is overall very good. A number of papers have been published in high impact journals such as Journal of Clinical Investigation, PNAS (USA), Blood, etc.

-Excellent financial support from competitive funding sources such as EU grants, ANR, PHRC.

-Dynamic, creative and efficient management of the unit by the past and current directors.

The very significant number of common core facilities that are in place to guarantee the development of many of the projects proposed.

-Good interactions between the different teams, between the teams and the plateforms, and between researchers from research organizations and clinicians.

-The close interaction with the clinical centers in the hospital is a major strength in terms of development of clinical translational programs.

-Good attractiveness and ability to recruit young and promising French researchers.

 Weaknesses and threats

-Some teams presented too many projects, and some of them may be risky.

-Some teams appear somewhat vulnerable despite good funding, and will require particular attention from the director.

-Some projects such as the search for new markers involved in tolerance could be intensified, although success in this aim is not guaranteed, without a deeper understanding of the underlying biology.

 Recommendations to the head of the research unit -Make additional efforts to attract young research fellows from abroad.

-Give particular attention to some teams that has been recently reorganized or may be more fragile due to the novelty and the risk of some projects.

-Brainstorm with the team leaders to help reduce the number of projects developped and concentrate on the more original and/or promising research avenues. In that respect, an in-depth evaluation of the pros and cons of the xenograft program should be carried out taking into consideration the recent advances in the field and in the unit. This research unit was initially founded by Jean-Paul Soulillou and has become over the years a leading one in Europe in the field of allo and xeno-transplantation. The scientists from this unit organize the yearly international NAT meeting, which has gained international recognition and at the same time reflects back positively on the unit itself.

 Production results

A1

The structure is stable, attractive to new scientists and highly productive. The number of publications per year over the last 5 years ranges from 31 to 55. Half of the publications in peer-reviewed journals are in journals with an impact factor > 4. Based on the past results, the publication record and visibility, the relevance and the impact of the projects presented, the committee scored 4 out of the 6 teams as excellent or very good. The publication record of these teams is of high standard and, perhaps more importantly, some of these published data represent original and are regarded as important contributions to the field.

Given the 'biomedical'-orientation of the research unit and its location in a clinical setting, it is important to highlight that a great deal of energy was devoted to establish successful translational projects going back and forth from bedside to bench to bedside.

The vitality of this research structure is obvious and much credit has to be given to the director who has maintained and developped a setting favourable to the development of ambitious translational research programs.

The remarkable success in raising funds allows the different groups to tackle ambitious scientific and medical questions, to develop cutting edge projects, and to implement new technical platforms.

Training has been very active in the unit and, in particular, over the last 5 years 33 PhD Thesis have been granted while an additional 24 are ongoing. 10 researchers and 5 Engineers have been recruited or attracted to the Unit since 2006.

A network of international collaborations, some of them funded by the EU, consolidate the international visibility. This international link is also attested by the Center of Excellence label given to the Unit by FOCIS. An additional success of the unit lies in its strong links with socio-economic partners, in particular biotech companies.

In conclusion the committee felt that the "Transplantation immunology and immune intervention" unit is a very good, healthy, and dynamic research center with a scientific production of international relevance and a clear thematic focus.

 An assessment of the results

The team is working in the field of dendritic cells (DC) and tolerance.

-Firstly, they have studied the biology of DC subsets and particularly the role of plasmacytoid dendritic cells to induce regulatory T cells. They have studied the role of TRANCE in the T cell/dendritic cell cross talk. From this work, five major papers have been published and two are submitted.

-The role of dendritic cells in allograft tolerance has been also studied, particularly the mechanisms associated with use of autologous dendritic cells. New immunoregulatory molecules have been characterized. These include, a role of CLEC-1, a C type lectin receptor, as well as the identification of TORID and HO-1 in the induction of tolerance. Five major papers plus 1 submitted have resulted.

-In parallel, the interaction between CMV infection and dendritic cells and particularly the role of DC-SIGN in the capture of CMV as well as the role of DC SIGN soluble isoforms during CMV infection and in the anergy of DCs have been analyzed.

-Other results emerge from studies in more translational and clinical research. Two directions are followed: the use of DC-modulators for inducing tolerance in different transplantation models; and the role and phenotypic features of dendritic cells in disease, particularly in the context of ANCA associated vasculitis.

Overall, numerous publications have been generated in good international journal such as American Journal of Transplantation, Blood, Cancer Research, Faseb J., Journal of Immunology.

The partnership within this team is strong and of good quality.

During the last 4 years, 4 M2R and 9 PhD students have been graduates, 3 PhD are in progress.

 Assessment of the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The team is recognized at the national, European and international level. One of the leaders is President of CFCD (French Club on Dendritic Cells). Numerous collaborations are ongoing in France, Europe and South America, and members have diverse invitations to national, European and international conferences and symposia.

The team has been able to recruit some students and postdoctoral workers and also one permanent position at INSERM.

The team has been very successful in raising grants (European grants, ANR, ARC, Ligue, Roche Foundation, Centaure, FRM).

 An appreciation of the strategy, management and interactions of the team

The strategy of research and for fund raising is good. The quality, management, interactions and spirit of the team appear excellent.

 Appreciation on the project

The project is a logical continuation of the previous activities.

-One part is focused on the biology of DC and the identification of mechanisms associated with allograft tolerance particularly the role of CLEC-1 and TORID molecules in the process.

-Because they have characterized and produced tolerogenic DCs, one project will be to implement a clinical trial for inducing tolerance in kidney transplantation. This project is a well-planned translational research project.

-Another project is to continue to study the role of DC during CMV infection. In this setting, a 3-D culture system has been developed to study the interaction of CMV with different DC subsets.

-Finally, another project aims at studying the cytokine interleukin-22 BP and its interactions with dendritic cells particularly in ANCA-associated vasculitis.

Taking into account the excellent expertise of the team, these projects are ambitious and feasible, albeit somewhat diverse. The project on CMV although well developed is not an obvious fit to this team. The project concerning the use of dendritic cells for inducing tolerance will require continuing efforts and will need a committed contribution from the team within the cell therapy section.

 Conclusion :

-Summary

This team has a strong expertise in the characterization of tolerogenic DCs and the use of molecules capable of inducing tolerance in transplantation using different animal models. They have also a strong drive to take their research from bench to bedside. Although of high quality, some projects will need to gain more focus, and while others may need to take a lower priority.

The committee felt this is a very good team.

-Strengths and opportunities

Recognized expertise in dendritic cells subsets.

Excellent knowledge in the field of immune tolerance.

Good ability to raise funding.

-Weaknesses and threats Too many projects albeit of good quality.

Some priority should be given to the most innovative and productive projects.

Some projects appear a little remote from the main expertise of the team.

-Recommendations

To focus the research on more fundamental aspects to better exploit the role of new molecules involved in the induction of tolerance, and to better understanding the mechanisms involved in the tolerance induced by dendritic cells. Studies with interleukin 22 BP should be developed.

 Title of the team: Immunoregulation in organ transplantation



 An evaluation of the productivity

The team has developed a unique expertise on generation of transgenic and, more recently, gene-KO rats using zinc finger nucleases. In the past 5 years, they have been at the leading edge of this technology. They have generated a number of transgenic rats, and one gene KO strain, which have proven useful for a range of mesenchymal stem cells, gene-therapy and xenotransplantation studies.

Another project developed in this team is to analyze tolerogenic mechanisms during transplantation, especially the role of CD8+ regulatory T cells and of DCs, and of the activity of heme oxygenase I (HO-I) in tissue protection. Here also, the team has successfully developed a number of original projects: for example, they are one of the few laboratories to be studying the action of CD8+ Tregs.

Altogether the overall rate of publication is very good.

 An assessment of the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The team leader was an active participant in an international collaboration worldwide establishing the zinc-finger-based gene KO technology in the rat (one Science paper in 2009), has edited several books or issues for international publications ("Methods in Molecular Biology" and "Current Gene therapy"), has been committee member and/or coorganizer of several European or international scientific societies and meetings on transplantation, and serves on the editorial board of several journals: he clearly has good international visibility.

The team has hosted many international students and one post-doctoral researcher for short training periods. Currently, only one French post-doctoral fellow is working within the Team. With the emergence of the new gene knockout technology, the attractiveness for foreign students and post-doctoral workers is likely to be much greater.

The team leader is also member of several local committees and has established partnerships with several biotech companies, enabling the transfer of expertise and technology (genOway,Hycult), as well as a IBiSA platform able to provide a real service to other laboratories.

Local and national collaborations are well developed.

 Comments on the strategy, management and interactions within the team

The way the team is managed and the interactions between team members are excellent.

The productivity is very good, with one or two articles per year (or even 5 in 2010) in international transplantation or immunology journals (impact factors 3-6), plus one article in a very strong journal in 2007 (J Clin Invest, IF 16,8) and in 2009 (collaborative work on technology of KO rats, Science, IF 28).

 An evaluation of the project areas

Three principle projects which are currently pursued are: (1) development of genetic modifications in rats and application to other animal models (e.g., pig); (2) prevention of immunogenicity to therapeutic genes and the optimisation of pre-clinical gene therapy treatments in inherited liver diseases;

(3) analysis of regulatory CD8+ T cells at the functional and biochemical level, especially in transplantation models.

The three projects are well structured, each under the supervision of distinct group leaders and two of whom are young scientists recently appointed into full time research positions at INSERM. The expertise of each group leader in their specific area is very good, and the projects are well designed and planned.

There was however some discussion amongst the reviewers that the structural work associated with TCR-peptide-MHC interactions, although technically elegant, may be delaying the studies needed to understand the mechanisms of suppression.

There was also enthusiasm amongst the reviewers for the team to exploit the use of the gene-modified rat technology for development of conditional KO rats, shown feasible by the success of the pioneering zinc-finger nuclease studies.

 Conclusion :

-Summary

The committee felt this is a very good team.

-Strengths and opportunities

The team is well integrated within the unit.

The team has a very strong and unique expertise in transgenic and KO rat technology, and in rodent transplant biology.

The team has 2 other ambitious projects (CD8+ T regs, and gene therapy in genetic liver diseases), which can benefit enormously from the successes of the other projects, and from the transgenic rat technology.

-Weaknesses and threats

It might be useful for the team to evaluate which directions will be the most productive for the very interesting Treg project, with the possibility of giving more focus to the mechanistic studies.

-Recommendations

We consider this to be an effective team likely to make important contributions in their 3 distinct arenas of research.

 Title of the team : Costimulation blockade and animal models

 Appreciation on the results

The overall main objective of the team is to develop novel therapies of costimulation blockade to be able to get rid of immunosuppressive drugs with strong side-effects in organ-transplanted patients, such as calcineurin inhibitors. This is a long-term goal of the team which was initiated in 2002. The major approach is CD28 blockade using an innovative agent produced by the team, sc28AT, a chimeric human/primate monovalent fusion antibody which competes with CD80/86 for binding to CD28. This reagent has the major advantage to be devoided of superagonistic activity because it cannot induce CD28 receptor cross-linking. It also preserves CTLA-4-dependent immune regulation. This is an extremely promising approach with potential high medical impact. It is also an example of public/private partnership as the development and valorization of the drug is carried out in collaboration with a biotech company (TcL-pharma).

Other research topics studied during the past 4 years include :

-LAG-3 as a target of activated alloreactive T-cells in organ transplantation. This topic has been developed in a rat model after having produced LAG-3-specific antibodies (patended by INSERM and licensed by Immutep, a biotech company devoted to LAG-3). However, this approach may also deplete regulatory T-cells expressing LAG-3 thus preventing tolerance induction.

-Acute vascular rejection in a baboon model, targeting the classical complement pathway by using a recombinant human C1inhibitor (rhC1INH) in collaboration with the Pharming company (Netherlands) which developed the molecule and allowed its use in novel models of presensitized pig and baboon allograft recipients. This is part of the XENOME FP6 European project.

-Related to the previous topic, one co-leader of the team is coordinating the LGA platform (Laboratoire Grands Animaux), which has been essential in the development of pre-clinical models for allo and xenotransplantation projects.

The laboratory fulfills all requirements in terms of operating procedures and ethical rules and will soon apply to an IBiSA accreditation.

There is an excellent publication record and many communications and awards showing an high visibility of the team, both nationally and internationally. Namely, in the past 4 years, the team published 11 original publications with one of the 2 group leaders as last co-author, including 2 publications in J. Immunol. and one publication in Science Translational Medicine in 2010 (Poirier et al.). This last publication is considered very important in the field with numerous (40) press releases. They have been associated to 17 other publications as collaborators mostly with other teams of the unit. 5 patents have been filed, 4 of which have been licensed to biotech companies (IMMUTEP, Paris and TcL Pharma, Nantes).

Partnership is strong, this team is very well integrated within the unit and developped numerous collaborations trough the LGA platform and the FP6 XENOME project. 3 PhD are underway, one post-doc is currently in the team. There is a good technical staff with 5 technicians or engineers, 2 holding permanent positions.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

Visibility of the team is very good at the national and international level. One of the team leaders is presently Director of the ITUN in Nantes (Institut de Transplantation-Urologie-Néphrologie). He is a member of the board of the Faculty of Medicine council, of the Société Française de Transplatation and of the ASSIM (Association des enseignants en Immunologie). As a Professor of Immunology at the Faculty of Medicine he has teaching duties and coordinates Immunopathology teaching modules. One of the team leader is Director of Research at CNRS but also has teaching duties.

He received an FRM (Fondation pour la Recherche Médicale) award in 2008. Among international symposia and conferences, one team member has been consultant for WHO regulatory requirements for Xenotransplantation (Changsha, 2008). One tema member gave a lecture at the American Society of Transplantation meeting (Miami FL, 2008) at the New key Opinion leader meeting of the Transplantation Society (Cape Town, SA, 2007). Currently there is one very productive post-doctoral fellow in the team and 3 PhD. Attractiveness can be assessed as good but could be improved in the future.

The capacity to raise funds is very good with an extensive list of grants obtained during the past 4 years, including 3 ANR grants, 2 for CD28 blockade proof of concept and develoment in 2005 and 2010 and one for LAG-3 targeting in 2008.

Grants were also obtained from Agence de la Biomédecine ( 2006), association vaincre la mucoviscidose (2010), DHOS INSERM (2009) and FP6 EU program XENOME (2008-2012). Funding from the Centaure foundation, TcL Pharma, Immutep and ROTRF have also been obtained, essentially on the anti-CD28 project. The team is also leader in an FP7 application presently under evaluation, TRIAD (Tolerance Restoration in Autoimmune Diseases).

On of the team leaders is co-founder of TcL Pharma, a biotech company created in 2007 with currently 9 employees.

 Appreciation on the strategy, management and life of the team

The management is very good and could be viewed as an example of co-leadership between a basic scientist and a clinical immunologist. This may be considered pivotal in the success of the team towards development of innovative therapies. The emergence of cutting edge projects is clearly apparent and evidenced by the success in getting competitive grant applications (3 ANR grants within the past 4 years, DHOS-INSERM 2009).

Both co-leaders actively participate to teaching at master (Nantes, Paris) and PhD levels. On of them participates annually to the HESPERIS European course.

 Appreciation on the project

Different projects have been presented by the team leaders, in line with their previous activities.

-the CD28 antagonist project was especially developed and is the main focus of the team. The team showed that sc28AT, a monovalent CD28-specific antibody, not only inhibits T effector cell activation but also increased Treg suppression in vivo. This effect was explained by a CTLA-4 dependent inhibition of Teff-APC contact while Treg-APC interactions were preserved. In collaboration with Maryland University, the team showed a preclinical efficiency of this therapy in baboons (Poirier et al., 2010). Interestingly, there was a synergistic effect between CD28 blockade and tacrolimus allowing to stop the immunosuppressive drug and inducing a state of operational tolerance. The committee was convinced by the relevance and originality of this approach. The project will be followed by : o improvement of the CD28 monovalent antibody through pegylation (ANR grant).

o basic aspects to get a better understanding of the molecular mechanisms underlying the CD28 antagonist properties.

o better define the therapeutic associations (CNI, MMF, mTor inhibitors) in the preclinical model of kidney transplantin baboons.

o ultimately, a phase I clinical trial so that a phase I/II in kidney transplants using a GMP-grade CD28 antagonist could start in 2012.

-The other projects include :

o LAG-3 Mabs as agonists or depleting agents of activated T cells, taking into account the concern about Treg depletion as well. A model of skin hyperesensitivity assay has been set up in primates (ANR grant).

o Use of rhC1INH to control humoral rejection in allo and xenotransplantation (XENOME FP6 project). The concern raised by the committee on this project relates to its current relevance given the beneficial effect of the C5-specific antibody (eculizumab) already in the clinics.

The different projects seem feasible and ressources appear to the committee adequate with regard to objectives (human ressources, collaborations, grants).

-Conclusion :

This team is a leading force in the field of biotherapy using antagonists of T-cell co-stimulation in transplantation. The committee was impressed by the work achieved and by the innovative and very promising approach using CD28 antagonists in transplantation. The publication record of the team is of international standard. In addition, the team leaders were able to establish national and international collaborations with excellent teams to implement their research.

The committee felt this is a very good team with an excellent development to the clinic.

-Strengths and opportunities

Excellent interactions from basic science to translational research and ultimately to the develoment of therapies with a major medical impact in transplantation.

Quality of management.

Excellent success in grant applications.

-Weaknesses and threats

The projects involving the use of rhC1INH to prevent humoral rejection and the one investigating the therapeutic potential of LAG-3 targeting were found to be less promising. A brain storming on the rationale and feasibility of such transfer in the clinic as they were presented should be initiated.

-Recommendations

The recommendation was to put priority on the CD28 antagonist program and to build as much as possible mechanistic and basic research on it.

 Title of the team : Immune reaction in allo-response tolerance/chronic rejection and in autoimmune-response/Multiple sclerosis"

 Team leaders: S. BROUARD / D. LAPLAUD Team 4 is focused on two main immunological topics related to allo-response tolerance in the context of chronic rejection and to autoimmune response specifically involved in multiple sclerosis. The team leader is mainly implicated in the first research program and has a smaller leading contribution in the second new research axis, which benefits of the competence of physician-scientist. The interaction between the two groups is based on use of similar experimental approaches on the role of B and CD8 T cells in the two main pathologies analyzed.

 Staff members

Past

 Appreciation on the results

This is a large team within the INSERM U643 laboratory. It evolved from the original team towards 2 main translational research topics :

-lymphocyte regulation in tolerance and chronic graft rejection, taking advantage of the concept of operational tolerance, i.e. patients having stopped immunosuppressive treatments and with no loss of the transplanted organ. This is a rare situation in kidney transplantation. The laboratory initiated studies on the immune status (mainly B and CD8 T cell compartment) of these patients in 2004, and was a pioneer in collecting biologicals samples from these patients, having the largest collection to date (n=27). The situation of operational tolerance is much more common in liver transplantation, a topic the team began to study in collaboration with the Sanchez group in Barcelona.

-Immunopathology of Multiple Sclerosis (MS). This topic was more recently introduced in the team. Albeit the 2 topics could appear somehow disconnected, they actually share common concepts (immune regulation and tolerance, antigen specificity of allo or auto-immune responses, role of B cells in immunopathology) and common tools (T-cell repertoire analysis, functional TRAP assay).

The publication record is very good. 92 original publications with 51 papers in IF>4 journals including the best speciality journals in Transplantation and Nephrology (Am.J. Transplant., IF 6.6 ; J. Am. Soc. Nephrol., IF 7.5 ; Kidney Int., IF 6.4), Immunology (J. Immunol. ; IF 6) and Neurology (Brain, IF 9.6). There are 2 publications in high impact journals (S. Brouard et al., PNAS 2007 andL. Michel et al., JCI 2008). Subsequent dissemination of the data were done through numerous reviews and editorials (Transplant. Int. 2006 ;NEJM 2006 ;Trends Transpl. 2007 ;Front. Biosci., Nat. Clin. Pract. Nephrol. 2008 ;Transplant. Int. 2010).

Due to efficient interaction with the other teams of the unit, this team has provided some important ressources such as the DIVAT collection and database (Données Informatisées et Validées en Transplantation), which are shared with other clinical centers involved in Kidney Transplantation (Paris-Necker, Nancy, Montpellier, Toulouse, Lyon-Herriot). The DIVAT biocollection received an IBiSA national platform label.

In the context of an expert clinical research, the team has developped an excellent valorization activity leading to 6 patents since 2005 (2 of them licensed). Moreover links with biotech companies, especially TcLand, TcL-Pharma and TcL Expression, co-founded by members of the team are very tight.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners.

The team has gained a very good visibility at the national and international levels. Three researchers joined the team between 2009 and 2011. The scientific expertise of the team leader is nationally recognized as she has been invited as a member of the INSERM CSS7. Permanent members of the team have received several awards (i.e Transplantation Society Award for "Outstanding Achievement in Transplantation Science",…) and have given invited lectures, mainly focused on transplantation and immunology, at high-level scientific meetings (ECI 2009, 13th International Congress of Immunology, 2007, World Congress of Nephrology, 2009). Moreover, the team leaders founded the world renowned and successful NAT (Nantes Actualités Transplantation) meeting. There is also a large number of publications in newspapers in the field of Transplantation and Ethics with a large audience at the regional (Ouest-France) and national level (Le Point, Le Monde, L'Expansion, …). The group working on MS immunopathogenesis is more recent but has already gained some international visibility.

The ability of this team to get funds at the local (TcLand, DRC), national (Agence de Biomédecine, Centaure, PHRC, ANR) and European (EU program "Indices of Tolerance" 2003-2008;EU program FP6 "RISET" 2005-2010) levels is excellent.

 Appreciation on the strategy, management and life of the team

Management of the team is very good. There is a good balance between basic and more clinically oriented research

 Appreciation on the project

The project is very large, patient-dependent and ambitious. It carries many excellent aspects but some others could be more challenging and risky. Overall, the balance between « low » and « high » risk projects seems good. Most of the projects appear feasible within the next 4 years to the committee, and should be productive.

Regarding the Organ Transplantation group, the committee was much impressed by the quality of the interactions between basic and applied research. Clearly this is a strength of the team, which needs to be further supported. Basic research projects focus primarily on the concept of « regulatory B cells » and their role in tolerance. Mechanistic approaches depicted are appropriate. They involve cell characterization using transcriptomics, as well as in vitro and in vivo experiments with international collaborations (for humanized mice model of human skin graft transplantation). More applied research will include the goal to define a composite score to predict Tolerance vs. Chronic antibody-mediated rejection. Achieving this goal would be of high medical impact in patients monitoring. The score will associate molecular, histological, and clinical parameters. It has been funded by a PHRC national grant and DHOS/INSERM. It is not an easy task but, in Europe, this team is one of the very few that could achieve this goal by performing the efficient « core » association between Clinics, the DIVAT bio-bank and database, and the collaborations for microarrays and tissue array on kidney biopsies. Biostatistics will be obviously one central issue in the project.

About the Neuro-Immunology program, the main objective is to get a clue on the myelin antigens giving rise to the deleterious T-cell reactivity. Other international groups aim to identify the target antigens in the development of this disabling disease. Experimental approaches will consist of T-cell repertoire analysis using the spectratyping technique developed at TcL Expression. One original goal is to compare T cell profiles from samples obtained directly from the cerebrospinal fluid and those from peripheral blood, by using an innovative assay developed by the group: the "TRAP" (Tcell recognition of APC by Protein Transfer) assay based on the trogocytosis phenomenon to analyze T-cell reactivity against autologous APC. Issues about the role of B-cells will also be investigated in collaboration with the team leader group. This is a good example of the rationale for these 2 partners to remain associated. This project is well supported by grants and seems feasible in the coming years.

 Conclusion :

-Summary

The committee felt this is a very good to excellent team in many aspects. This team has a leading position at the national and international level in immunobiology of renal transplantation built on an outstanding network of collaborators, a long-term prospective biobanking and database collection (DIVAT), and an exceptional ability to raise funds and develop partnership with Biotech companies. The group working in MS immunopathology, albeit more recent, has already proven very successful.

-Recommendations

Given the visibility of the team, it could attract more post-doctoral fellows from abroad. The committee appreciates and encourages efforts made to improve mechanistic lines of research, as for instance the role of B cells in operational tolerance and the development of collaborative projects with team 2 for animal models (BANK-1, XBP-1 KO mice, CD32b transgenic rat). This is even more the case for the Neuro-Immunology projects which should be clearly hypothesis-driven and focus on MS immunopathology. Given the size of this group, the development of projects in other directions (astrocyte-lymphocyte interactions) should be discussed.

 Appreciation on the results

Several objectives of the team, in particular "mechanisms of endothelial dysfunction in Transplantation" or "characterization of anti-HLA and non HLA antibodies in the chronic kidney allograft rejection", are relevant and may be useful to the improvement of patients' treatment. Other projects relate to the pathophysiology of kidney diseases or target important translational questions.

During the last 5 years one of the Team leaders demonstrated good productivity in publications with papers appearing in good quality scientific journals (IF between 4 and 10) and in senior position (last author in J Biol Chem, 2006;Blood, 2007;Arterioscl. Throm, 2008;PloS One, 2009;Biochemical Pharmacology;2010). Her scientific production is highly associated with endothelial cell signalling. Several publications in collaboration with other Teams from the Centre attest to the collaborative spirit. Althogether the overall rate of publication is good.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The attractiveness of the team and its international visibility could be improved, beyond the one post -doctoral fellow currently working in the Team.

Of note two past PhD students received an award from the fondation Bettencourt Schueller.

The team has won numerous institutional grants from ANR, PHRC, from Agence de la Biomedecine, and from Regional agency (Pays de la Loire) that should highten progress on all projects described. In addition, the team leader contributes to one EU-funded integrated project (Xenome).

No public-private partnership is described, but the team has submitted one patent on biomarkers of allograft rejection in 2009.

 Appreciation on the strategy, management and life of the team

The scientific productivity of the Team is good and reflects the capacity of the team leaders to manage their research work. Since 2006, 8 PhD Theses were defended and 4 are ongoing. The main lines of research may certainly benefit in the future from further interactions within and outside the team. A dynamic new investigator has joined the team in 2010. It is a clear ambition of the laboratory to promote nephrology as a strong domain of research. Therefore, by focusing their efforts on fewer projects the Team would be more competitive in establishing the pathophysiology of the disease processes they are investigating.

 Appreciation on the project

The common aim of the research in this Team is to investigate the role of antibodies and complement in nephropathies and kidney transplantation. The endothelial cells and the podocytes are the targets for the experimental part of the projects. Most projects are a continuation of previous work.

The projects investigating the mechanisms underlying endothelial dysfunction in Transplantion are well constructed and benefit from well-recognized internal expertise. The MHC class I-related chain A (MICA) molecules exist as membranebound and soluble isoforms and are encoded by a polymorphic gene. The project is to study the functional impact of MICA in kidney transplantation (polymorphism or isoform). Given the demonstrated importance of MICA in immune pathways, the project is of clear interest but of limited ambition. A considerable amount of research time has been invested in studies aimed at elucidating pathogenic processes that causes endothelial cell injury and ultimately bring about the biological cascade(s) that lead to the pathologic vascular changes. The team has acquired an expertise on endothelial cell signalling pathway and should take advantage of this recognized strength to reach an even higher level of scientific quality.

The team has unity in that all the PIs work on kidney diseases, but seems to target quite diverse topics. Each PU-PH works on his/her own project ie a given kidney disease or transplantation. The project aiming at better understanding the mechanisms leading to recurrence of idiopathic nephrotic syndrome is important, but could prove difficult as many molecules or cells (role of immature cells) seem to be implicated. However, no candidate markers have been identified since the first report by the group in 1998 that Protein A immunoabsorbtion improves the disease. For this project, state of the art technology will be used, and this could allow a breakthrough provided enough resources are invested. The recruitment of a full time scientist would help for the success of this competitive project. The expertise of the group in transplantation is recognized and it is important for the clinicians to demonstrate the value of the knowledge gained in biomarkers associated with kidney allograft acceptance and rejection. In that respect, a translational project on the characterisation of donor-specific antibodies (DSA) is closely linked to a clinical trial (PHRC and ANR-Emmergence bio).

The project presented by the newly recruited physician-scientist stems from results obtained prior to joining the Team. His project is original and connects endothelial cell injury observed in kidney disease to VEGF and to Flt-1 activation, an endogenous inhibitor of VEGF. He also has expertise in complement and its possible role in endothelial cell activation and kidney allograft rejection.

Resources allocated to each project are reasonable, and clearly demonstrate the motivation of all members of the team to raise the necessary funds.

 Title of the team : Neuronal differentiation and neuro-immune interactions: application to intracerebral transplantation

 An assessment of the results

The team 6 has focused its interest on three main topics related to the evaluation of different intracerebral transplantation protocols in rodents and non-primate humans. Special attention was devoted to assess experimental approaches reducing the cell rejection in animal models of Parkinson's disease (PD). Most of the projects deal improving the efficacy of this strategy by reducing the potential deleterious immune response.

In 2011 the team was composed of at least 10 persons (3 CR1 INSERM, 1 MCU, 1 PU-PH, 1 engineer, 1 assistant engineer and 3 PhD students). Within the last two years, the team diminished in numbers due to the retirement of one Inserm DR1 and the graduation of 2 PhD students. Thus two new students should be recruited.

The work of team 6 is organized into three related but independent parts:

-The first part is dedicated to the development of appropriate protocols to graft neurons into diseased brains, with a particular attention to PD and the rescue of the degenerating dopaminergic neurons. This subject, at the interface between transplantation domain and neurosciences, is potentially high impact, but also high risk. The committee found it appropriate that such a high-risk project has been undertaken in a center with strong technological and scientific expertise in the domain of transplantation. In this fruitful scientific environment, the team has not only used existing methods, but also developed innovative tools, to evaluate therapeutic strategies in animal models of PD, including primates. The results, although short on information on fundamental mechanisms, basic approaches, showed that the strategy has promise with a convincing recovery rate of treated animals.

-The second part relies on the production of a transgenic rat model of PD by over-expressing the a-synuclein gene under the control of a dopaminergic specific promoter. The rationale of creating this rat model is that "rats infected by asynuclein-expressing virus showed some motor impairments associated with partial dopamine neuron cell loss". In this rat model, substantial alterations of olfaction have been detected. Despite this, it has not been possible to identify strong phenotype related to the degeneration of dopaminergic neurons within the mesencephalon . This 'transgenic' project has allowed the team to raise at least two grants, but the major results of this time-consuming project have not yet been converted into a significant publication.

-The third part is a new analysis of the potentialy interesting role of immune proteins on neuronal differentiation. Expression of CD3z has been detected in neurons and a mutation of this protein was found to alter some aspects of the differentiation of cultured neurons.  An assessment of the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

During the last four years, the team has established collaborations related to the analysis of animal models of PD (INRA; Nouzilly France, MIRCeb; Fontenay aux Roses, CORIT; Padova, Italy). Moreover researchers from this team participated efficiently in the FP6 program XENOME devoted to transplantation. They have obtained regular fundings through regional (Centaure, Région de Loire) or national funding agencies (AFM, France-Parkinson, Fondation de France or National Research Agency). However these longstanding international collaborations led to only limited scientific exchanges. The team has efficiently trained several Master and PhD students but no post-poctoral fellow. This last aspect appears surprising because the team has been regularly well-funded but might be explained by the lack of funding for the coming years. In addition, the team members have only participated in two international conferences, presenting just that part of their work that, it seems, will be discontinued. However some members have given several popular science seminars in France. The committee felt that the team leader should try to improve his international presence within the next four years.

 An assessment on the strategy, management and life of the team

Based on their previous results the team has planned to undertake three different subprojects. Two are related to PD and one to neuronal differentiation. Cross talk between research projects focusing of very different aspects of neuronal function and dysfunction might be fruitful, but the rationale of having a project related to neuronal differentiation within this team was not completely clear to the committee. It appears though, that one of the projects of the latter sub-team aims at understanding mechanisms involved in the recovery in models of PD. To achieve this ambitious goal, the team will remain stable in its complement of permanent researchers, and will recruit new Master and PhD students. Until now the team has regularly trained PhD students with publications emerging prior to their thesis defense. The permanent researchers have regularly published their results in good international journals, but probably due to the necessarily long duration of some of their readout systems, the number of high level publications are limited.

 An assessment of the project

The team projects were based on the three directions emerging from their earlier work. The first part of the project aims at strengthening the therapeutic strategies of PD that they already evaluated. The committee was convinced that this strategy could have some important outcomes in the near future. It seemed however, that the understanding of the molecular and cellular mechanisms involved in the recovery phase was limited. The committee recommends a deeper analysis of underlying mechanisms. With regard to the rat model of PD, it was not clear to the committee why the model had been pursued so actively, given the somewhat disappointing results. The committee recommend some prioritisation of key experiments that would allow Go/No Go decisions. The third sub-project intends to further investigate the role of 'immune' proteins in the differentiation of neurons. The committee felt that there was a need to define improved control experiments that would allow to precise localisation of these proteins, and the involvement of non-neuronal cells in the observed neuronal phenotypes. In addition, some projects of this subgroup appear a little distant from the main topic of the team. The committee recommends refinements of project choice so as to be to the central interests of the laboratory. This might allow this team to benefit from the dynamism of the whole laboratory.

 Conclusion:

-Summary

The committee felt this is a good team.



  Date and execution of the visit

:

  Number of permanent researchers with teaching duties (recorded in N1) who are active in research 12 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 13 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 4 A5: Number of PhD granted during the past 4 years 40 3  Specific commentsThe research unit is a middle-sized biomedical research institute including mostly teams centered around the immunobiology of transplantation and immunotherapy.

4

  Appreciation team by team  Title of the team: Biology of dendritic cells and immune tolerance

  of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 4 4 N5: Number of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 2 2 N6: Number of Ph.D. students (Form 2.7 of the application file) 4 4 N7: Number of staff members with a HDR or a similar grade 1 1

  . The team appears to work smoothly. The team leaders are committed about the future of their PhD and post-doc fellows. PhD students have been successful for getting a permanent position in research, 4 in private companies and 1 in academic research as CR2 INSERM in 2010. Moreover the team attracted 2 researchers with a permanent position, including 1 CR1 INSERM and 1 DR2 INSERM.



  Title of the team: Endothelial and glomerular dysfunction: mechanisms and therapeutic targets  Team leaders: Ms. Beatrice CHARREAU and M. Jacques DANTAL The team has been created in January 2010 and includes members from three previous teams (team 7, team 9 and 3) and a new group. of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file) 1 1 N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 2 2 N5: Number of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 3 3 N6: Number of Ph.D. students (Form 2.7 of the application file) 3 3 N7: Number of staff members with a HDR or a similar grade 4 4

  The other Team leader has published two manuscripts in a senior capacity during the last 5 years on the subject of the idiopathic nephrotic syndrome (last author in JASN, 2009 and in AJKD). The newly recruited PU-PH in Nephrology (November 2010) trained at the Centre for Complement & Inflammation Research at the Imperial College in London. Despite the short time spent in Nantes, he has recently submitted a manuscript to J Am S Nephrol on the role of Flit-1 in ANCA positive vasculitis. Most publications of the researchers with teaching duties are clinical publications in the Journal of Nephrology.

  During the last 4 years, the team leader has published 4 articles in a senior role(J Neurosci Res 2006, 2009 ; Diffferentiation 2006 ; Exp Neurol 2010) and 3in penultimate position (Exp Neurol 2006, Mol Cell Biol 2008, Transplantation 2010), but the other researchers of this team have also published in first or last position (Exp Neurol 2006, Neurosci Lett 2006 ; Mol Cell Neurosci 2006 ; Mov Disord 2007 ; Mol Cell Biol 2008 ; J Cell Mol Med 2009 ; Transplantation 2010) in journals with fair IF (<5.9).

 Team leaders: Ms. Maria-Cristina CUTURI and M. Regis JOSIEN

	 Staff members	Future Past
	N1: Number of researchers with teaching duties (Form 2.1 of the application file)	1	1
	N2: Number of full time researchers from research organizations (Form 2.3 of the application file)	3	3
	N3: Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file)	4	4
	N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file)	1	1
	N5: Number of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file)	2	2
	N6: Number of Ph.D. students (Form 2.7 of the application file)	4	4
	N7: Number of staff members with a HDR or a similar grade	4	4

Statistiques de notes globales par domaines scientifiques

  (État au 06/05/2011)

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal

The scientific questions addressed by each scientist have clear clinical interest, but few novel and ambitious projects have been presented. The characterisation of molecules or cells implicated in idiopathic nephrotic syndrome is a high-risk / high-gain project, and more effort and resources could be invested in this project.

 Conclusion:

-Summary

The committee felt this is a good team.

-Strengths and opportunities

The team is well integrated in the unit. The PIs from this team have been able to recruit reasonable numbers of patients suffering from relevant kidney diseases. The team has a well known recognized expertise in transplantation, and has the capacity to promote clinical research at high level.

-Weaknesses and threats Too many projects have been presented covering a large field without apparent clear prioritization. This is the likely result of the recent organization of this Team derived from 4 different Laboratories, but should now be corrected.

-Recommendations

The aims of the research are highly guided by the specialization of the different PIs. However, the Team leaders should make all efforts to maximize those interactions. Some of the seemingly outlier projects could be restructured to gain strength and effectiveness, so as to allow better integration of the team as a whole. Whereas the productivity is good, the Team could further increase its impact by investing in more ambitious projects. The efforts of the group for developing translational research projects should be encouraged, in particular the collection of endothelial cell cultures from transplant donors need to be further exploited.

-Strengths and opportunities

The subject of this team is at the interface between neuroscience and transplantation. Therefore, this team can greatly benefit from the technical and scientific expertise of the whole laboratory. The team has the skills, tools, data and man power to significantly upgrade its impact and productivity in the next years.

-Weaknesses and threats Some sub-projects without clear rationale. Not enough investigation of the basic mechanisms.

-Recommendations

This team should strenghten its work on understanding basic mechanisms. The team should highlight key experiments that could allow Go/No Go decisions on some of the projects, and to then strengthen those projects that appear fruitful. The team leaders should enhance their international presence.


president Michel Cosnard

Éric Solary

In the name of HCERES, 1

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Chemistry The proposal is to create in Rennes 1 University a new research unit made of 2 teams and ~50 persons. This new unit will bring together researchers with complementary expertise in biology and chemistry. The director, Mr Éric CHEVET, and the deputy director, Mr Patrick LEGEMBRE, both migrated from Bordeaux in the recent years. Mr Patrick LEGEMBRE rapidly interacted with a group of chemists headed by Mr Pierre van de WEGHE and they progressively planned to set up a new research unit that combines multiple expertise. This new unit will be located at two sites, Eugene Marquis Cancer Hospital for biology aspects and the Campus of Rennes 1 University for chemistry aspects. The objective is to include medical oncologists, cellular and molecular biologists, and chemists in a unique structure aiming at developing new therapeutic approaches in cancer. Three main pathways are targeted: IRE-1 unfolded protein response, ING2-mediated DNA damage repair, and death receptor dependent non-apoptotic signalling. Chemists will create molecules that could interact with these signalling pathways when deregulated in cancer. This unit will be highly connected to an efficient federative structure (the UMS Biosit) that manages 14 core facilities on the Rennes 1 University campus.

Management team

Before submission of the application, the proposed directors, Mr Éric CHEVET (general director) and Mr Patrick LEGEMBRE (deputy director), decided to join their efforts with Mr Rémy PEDEUX and Mr Pierre VAN

Scientific domains

Oncogenesis, resistance to therapy, signalling pathways, immuno-oncology, medicinal chemistry, chemical biology, solid tumors.

Unit workforce

Introduction

The proposal is to create a new unit made of two teams by combining biologists, chemists and medical doctors aiming to identify targets and develop new drugs in the cancer field. These researchers were working in other environments so far. Two of them worked in another French town until recently, and found a common interest to associate their expertise with a group of chemists in an attempt to reach a common goal. Their unit will benefit from a federative structure (the UMS Biosit) managing all the needed core facilities and from interaction with medical oncologists.

Global assessment of the unit

Following the site visit and exchanges with the researchers and the funding bodies, the committee strongly supports the creation of this new research unit. This recommendation is based first on the quality of the team leaders and their research plans, the originality and interest of the questions raised, the strong wish to translate into clinics, the multidisciplinary approach that has been chosen and the strong support of the University and of the anticancer center in which most of the labs are located. A few weaknesses have been identified that can easily be overcome and should not preclude the success of the proposed programs. One of the challenges will be to efficiently coordinate biology and chemistry, which is actually already on-going with encouraging preliminary results, and to keep working the very good interaction established with clinicians by improving their embedding in the research activity. There is indeed a strong wish to translate the results of the research into clinical trials, patents and, when possible, start-up companies. This research unit may participate to the favourable evolution of the biological science landscape in Rennes 1 University.

Strengths and opportunities in the context

the science is of quality; -the structure is multidisciplinary, with biologists, chemists and medical oncologists working together;

there is a strong local support (from CLCC and Rennes University to the regional council and Rennes metropole);

the unit has original programs, solid proposals, with a very good to excellent background;

there is a conductor thread based on a common wish to identify therapeutic targets and synthesize related compounds.

Weaknesses and threats in the context

the proposal is a juxtaposition of scientific projects that could benefit from a stronger conductor thread;

the role of embedded medical scientists could be optimized.

Recommendations

maintain permanent scientific interactions between teams and between groups in the teams;

in such a configuration, progressively introduce medical doctor knowledge, beyond only providing tumor samples.

N4:

  Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (technicians and administrative personnel) N7: PhD students TOTAL N1 to N7 Qualified research supervisors (HDR) or similar positions 2  Overall assessment of the unit

  , Oncogenesis, Stress, Signaling

	1  Introduction
	History and geographical location of the unit
	Unit acronym:	COSS
	Label requested:	UMR
	Current number:	Creation
	Name of Director
	(2015-2016):
	Name of Project Leader	Mr Éric CHEVET
	(2017-2021):
	Expert committee members
		Mr Pierre COUBLE
	Representatives of supervising institutions and bodies:
		Mr Éric BELLISANT, Faculty of Medicine Université de Rennes 1
		Mr François GUILLE, Centre de Lutte Contre le Cancer Eugène Marquis
		Mr Claude LABIT, University of Rennes 1
		Ms Stéphanie POMMIER, INSERM
	Head of Doctoral School:
		Ms Nathalie THERET, Doctoral School n° 92 "Vie, Agronomie et Santé"

Chair:

Mr Éric SOLARY, Gustave Roussy Cancer Campus, Villejuif Experts: Ms Eleonora CANDI, Universita di Tor Vergata, Roma, Italy Mr Vincent DIVE, CEA, Gif-sur-Yvette (representative of INSERM) Mr Erwan POUPON, Faculté de Pharmacie, Chatenay Malabry Mr Frédéric RIEUX-LAUCAT, Laboratory of Immunogenetics and Pediatric Autoimmune Diseases, Paris Scientific delegate representing the HCERES:

  DE WEGHE to create a common structure. They proposed to organise the unit in two teams headed by Mrs Éric CHEVET/ Mr Rémy PEDEUX and Mrs Patrick LEGEMBRE/Pierre VAN DE WEGHE, respectively.

	HCERES nomenclature
	SVE1_LS4 Physiology, Physiopathology, Endocrinology
	SVE1_LS1 Molecular Biology, Structural Biology, Biochemistry
	ST4 Chemistry

signed by their chairman.


president Michel Cosnard

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Management team

The team is managed by a steering committee consisting of the director and co-director, a clinical representative and a local representative of the blood bank (EFS Bretagne).

HCERES nomenclature

SVE1_LS4 Physiologie, physiopathologie, biologie systémique médicale SVE1_LS6 Immunologie, microbiologie, virologie, parasitologie

Scientific domains

The team is performing preclinical research addressing normal and malignant B-cell differentiation and microenvironment, respectively, as well as clinical-translational projects on biomarkers in lymphomas, mesenchymal stroma cells and immune-modulation in sepsis.

Unit workforce

Unit workforce

Global assessment of the unit

The proposed unit Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC) is the continuation of the monothematic INSERM unit U 917 Microenvironment and Cancer (MICA). MICA has been successful in establishing a solid and promising basic and translational research program in immunology/hematology. The team has a strong and dedicated leadership and the program is well integrated with the Hematology Department of the Rennes University Hospital and the French Bloodbank (EFS). The necessary infrastructure and competence are in place or available through cooperations. Furthermore, the team consists of a number of excellent researchers and is actively involved in a number of national and international research activities, resulting in efficient collaborative networking. The high academic reputation of the group members is reflected by a number of invitations as invited speaker and participation in evaluation committees. In the last five years, the group has made considerable progress and gained an international reputation due to the high quality and impact of its scientific work. Main achievements have been made on the preclinical as well as on the translational side, with important contributions to the field. The quantitative scientific production has been very good to excellent with a total 52 publications (including original reports and reviews), of which the majority is directly related to the program. The unit is attractive to international applicants, and has trained a number of post-doctoral fellows and doctoral students. The success of the group is further documented by acquisition of considerable external funding, both nationally and internationally.

Strengths and opportunities in the context

MICA is a well-established and productive unit, providing a solid base to build upon and to generate an even stronger and improved research program in the proposed MICMAC program. Several points add to the strength of this unit, including an experienced and effective leadership and a long-standing expertise of its members in experimental hematology/immunology on an internationally competitive level. Furthermore, the unit is tightly connected to the clinical Hematology Department and the Bloodbank. This rare and close interaction between clinical and preclinical partners will allow the unit to perform important translational studies addressing clinically relevant questions related to the preclinical program. The program has an excellent network nationally and internationally and is highly visible through its publications. This certainly raises the chances to recruit outstanding students and young researchers to the program. Lastly, the group has started to establish relevant in vivo models, which can be key to take the next step towards publication in the highest top-ranking scientific journals.

Weaknesses and threats in the context

Despite the obvious strengths of the program there are some potential weaknesses that need to be taken into consideration when planning for the next phase of the program. Most of these weaknesses have been identified in a thorough SWOT analysis performed by the applicants and appropriate measures to address most of these issues have been suggested. Weaknesses from the SWOT analysis include the low number of full time researchers, the lack of very high impact publications, the lack of a hematopathologist in the team, the small size of the research unit and insufficient animal facility space and support. Additional weaknesses identified through the review process relate to the broadness of the otherwise well developed research strategy. Although the proposed research program is generally grounded in preliminary results and expertise of the lab, it is in some parts too vast for this relatively small research group, and the incorporation of new preclinical and translational research lines may lead to loss of focus. A more focused approach could improve the quality of the program and translate important findings into clinical studies.

Recommendations

The unit should maintain the same path of research that was successfully pursued in the last period. It is recommended to focus on the further development of the existing research rather than extend the translational part of the program. The basic research lines need to be strengthened by suitable in vivo models, some of which are already being developed. Furthermore, given the strong focus on human material, the recent development of suitable xenotransplantation models appears to be especially important. Lastly, the unit should aim to better integrate their successful translational program with the themes developed in their basic research program.

  Ms Susan CHAN, IGBMC, Strasbourg (representative of the CSS Inserm) Mr Thierry DEFRANCE, CIRI, Lyon Scientific delegate representing the HCERES: Mr Jean ROSENBAUM Representatives of supervising institutions and bodies: Ms Anne JOUVENCEAU, Inserm Mr Claude LABIT, University of Rennes Mr Pierre TIEBERGHEN, Établissement Français du Sang Head of Doctoral School: Ms Nathalie THERET, Doctoral school n°92 "Vie Agro Santé -VAS" 1  Introduction History and geographical location of the unit The unit Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC) is the continuation of the monothematic INSERM unit U 917 Microenvironment and Cancer (MICA), which was created in 2008 and renewed in 2012. The unit is located in a building of the University of Rennes, close to the Rennes University Hospital.

N4:N6:N7

  Other permanent staff (technicians and administrative personnel) 10 10 Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) 4 Other contractual staff (technicians and administrative personnel) 6 spent at least 12 months in the unit 6 Number of Research Supervisor Qualifications (HDR) obtained during the period 2 2  Overall assessment of the unit Introduction The monothematic INSERM unit U 917 Microenvironment and Cancer (MICA) was created in 2008 and renewed in 2012.The unit is located in a building of the University of Rennes, close to the Rennes University Hospital. The team addresses basic questions of normal and malignant B-cell differentiation and how the bidirectional interactions between the microenvironment and leukemic B cells impact on follicular lymphoma (FL) cell growth. Furthermore, translational projects include identification of lymphoma biomarkers and optimisation of clinical mesenchymal stromal cell therapy. The unit is co-affiliated with INSERM and University of Rennes 1. It has strong ties with the Hematology Department of the Rennes University Hospital and the French Blood bank (EFS). Furthermore, the unit belongs to the Research Federation (SFR) Biosit and is part of the Doctoral School Life, Agronomy and Health (Univ. of Rennes). For the next term, the unit plans to continue and extend its work in the monothematic research unit Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), now also including a line of research focusing on immune-modulation in a non-tumor setting, i.e. sepsis.

signed by their chairman.


Simon Wagner

Vito Pistoia

M Thierry

Jo Molina

Ms Marie Christine Bene

Aeres Scientific

M Jean Rosenbaum

Ms Christine Tuffereau

Observers

The visit took place in Rennes on November 16, 2010. The site visit began at 8:30 am by a meeting of the committee with the AERES representative.

From 8:45 to 11 am, the group leader and 3 team members introduced the general strategy of the lab and the projects. The committee then split into 3 subgroups in order to meet separately the PhD students, the techicians, and the scientists. The committe then met University, INSERM and other local representatives during 30 minutes.

At 1 :00 pm, the committee met for debriefing and drafting the report. The visit ended at 3 :00 pm.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The team as such was created as a monothematic INSERM Unit in 2008. It is located in a building of the University of Rennes, close to Rennes University Hospital. It is a small team, highly focused on the understanding of the role of the bone marrow and lymph node microenvironments in B cell lymphomagenesis.

 Management team

This small team is directly managed by its director. This is a young team that is well integrated in the context of the university hospital of Rennes. This team focuses its work on the pathophysiology of B cell lymphoproliferative disorders with a focus on the role of the stromal niche on B cell growth. The team is headed by a very charismatic director, an immunologist who is working in close collaboration with both the university departments of clinical and biological hematology. As a result of these collaborations they have built a strong structure, almost unique in France, involved in basic and translational research on B cell lymphoproliferation that will certainly develop in the future. However, an effort should be made to increase their research on more basic aspects of the normal B cell development and pathophysiology of B cell transformation to develop new hypotheses that they could confirm in human diseases. They have the capacity to integrate new teams of young promising scientists because of the high potential of their field of research, the intellectual potential of the leaders of this unit, the good scientific environment, the ability to work on human samples, and the space availability and good core facility. Actually, in this respect they have recently recruited a new young scientist who has identified new genes involved in B cell development that may play a role in B cell transformation. Hopefully with the reinforcement of this new scientist and others they will be able to publish good work in generalist journals with a higher impact factor than the best hematology journals in which they are already currently publishing.

 Staff members

 Strenghts and opportunities

This monothematic team focuses most of its efforts in trying to understand the role of the microenvironment on the development of B cell neoplasia. This topic of research is ambitious and this team is one of the international leaders in this field. They are well connected with European Networks. They have built a very strong and impressive network between the clinical hematological department, biological hematological department and their INSERM unit. This network extends to regional hematology centres that provide them with good quality samples for diagnosis and research. The leaders of these three structures are working well and synergistically together. As a result they benefit from a large number of patients samples that they can use for research purposes. From their work they have the capacity to go from the bench to the bedside and vice et versa. In the near future they will develop phase 1,2 studies based on their scientific works. The leader of this team has a very good scientific background and is well known in France as well as outside. The laboratory is very well organized in a very nice environment, with a good quality of work and complies with every regulatory aspect. No conflicts have been evidenced between students, technicians, researchers, and team leaders. This unit is supported by both the university and the hospital and is well integrated in both structures. In addition they have obtained a strong financial support from the city and they have been able to get funding from ANR, Ligue contre le cancer, Association contre le cancer, etc. They have a strong potential to grow up and to recruit new teams to develop more fundamental aspects of B cell lymphomagenesis and to promote researchers from inside to get a tenure positions either within an EPST or at the university. In this regard they recently recruited from inside a new CR1.

 Weaknesses and threats

The main weakness of this unit is the low number of basic scientists that could bring more insight to the molecular and cellular mechanisms of lymphomagenesis. For example, they should develop more basic aspects of apoptosis for some aspects of their work.

Probably partly as a consequence of this low number of basic scientists, they have not been able to publish in general journals with high impact factors.

In addition, most of their students and post docs have not yet published their work and do not communicate sufficiently outside their laboratory within the campus nor in national and international meetings.

 Recommendations

The unit should maintain the same pathway of research. However, it is strongly recommended to try to recruit new researchers in order to exploit the full potential of their field of research now that they have built strong basis to do so. Particularly they should develop some basic aspects of their research to improve their number and level of publications. The team has obtained significant findings in its different thematic axes. They demonstrated the role of the mesenchymal stromal niche in B-cell lymphoma pathophysiology. They were also able to generate clinical-grade human mesenchymal stem cells.



Since its creation, the team has published 23 publications strictly derived from their own research program, among them 12 with an impact factor above 5. This includes notably 2 publications in Blood (IF> 10), and others in Cancer Research, Leukemia, Oncogene, Journal of Immunology. They also published 22 articles as collaborative work and an additional 18 clinical publications. Given the low number of scientists, this is an excellent achievement.

Five PhD theses have been defended.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The team has an excellent national and international recognition. The team leader has been invited 10 times to give talks in meetings.

They have recently succeeded in attracting a young scientist to the lab, who was then recruited as an INSERM scientist, which indicates their attractiveness.

The unit has made a good effort to try to valorize their work by the deposition of patents. In addition, they have succeeded in connecting their work with the clinical investigation center, to develop new prognosis tools and new therapeutic strategies of B cell lymphoproliferation.

They have obtained a strong financial support from the city and they have been able to get competitive funding from the FP7 program (they are partners in two networks), ANR, Ligue contre le cancer, Association contre le cancer, etc. They have also obtained good research grants from biotechnologies and pharmaceutical companies.

In addition they have set-up collaborative work with the laboratory of the Etablissement francais du sang to develop new antibodies and to optimize the use of mesenchymal cells as immunosuppressive cells that they will try to valorize through collaborations with private companies.

 Appreciation on the management and life of the research unit

There are very good management and life in the research unit. A great organization in all aspects of regulation has been set-up.

The governance is well carried out with a strong and efficient collaboration between researchers and MDs. Members of the unit who are MD/PhD combine working both within the unit and with clinical and laboratory duties. They should push more their students and post docs to focus on their works to get publications and to communicate more outside the lab.

The members of the unit have a strong involvement in teaching activities in M2 and PhD schools, and medical university. In addition they have organized national and international workshops.

 Appreciation on the scientific strategy and the project Taken together the strategy of the project is clear. The team is and will remain focused on specific aspects of B cell lymphomagenesis, and they will try to develop more basic research within this field of research that may serve in the future to develop new prognosis markers, and treatments of lymphoma particularly targeting the microenvironment.

The project is overall a good project, with a sound design of their goals and experiments in the near future. The leader of the unit and her collaborators know where they are going and they know how to reach their goals. However, they should put more emphasize on deliverables, particularly on publications.



  Date and execution of the visit

  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 6 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 1 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 2 A5: Number of PhD granted during the past 4 years 5 3  Specific comments  Appreciation on the results

Sciences du Vivant et Environnement

				Statistiques de notes globales par domaines scientifiques
						(État au 06/05/2011)
		Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
		A+	7	3	1	4	7	6		2		30
		A	27	1	13	20	21	26	2	12	23	145
		B	6	1	6	2	8	23	3	3	6	58
		C	1					4				5
		Non noté	1									1
		Total	42	5	20	26	36	59	5	17	29	239
		A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
		A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%					6,8%				2,1%
		Non noté	2,4%									0,4%
		Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*
		Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	MICRO-ENVIRONNEMENT ET CANCER -MICA	A	A+	A+	A+	A
	C1	Qualité scientifique et production
	C2	Rayonnement et attractivité, intégration dans l'environnement
	C3	Gouvernance et vie du laboratoire
	C4	Stratégie et projet scientifique

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


president Michel Cosnard

Kathy Dujardin

In the name of HCERES, 1

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Comportement et noyaux gris centraux

Management team

The research unit is headed by Mr Marc VÉRIN. It consists of six senior members. Five of them are qualified research supervisors.

HCERES nomenclature

SVE, SVE1, SVE1_LS4, ST6

Scientific domains

The team is multidisciplinary. The fields covered are those of neurology, psychiatry, neurosurgery, neurophysiology and neuroimaging. It also integrates the methods of neuropsychology and biostatistics.

Global assessment of the unit

Considering the ratio between the number of publications and the size of the unit, the scientific quality is excellent with a good international outlook.

The unit is attractive and has a good academic reputation. It is involved in national and international projects as well as in local and national networks. Members are involved in training through research mainly through the supervision of PhD students. They will also be involved in a master degree during the next contract.

The ability to find public and private funding is noteworthy.

The unit has more than 20 projects for the five coming years. All are ambitious with a strong interdisciplinary dimension. However, this may be too ambitious considering the size of the unit and the fact that all members are clinicians and none of them is involved full time in research. There is a real risk of dispersion.

  location of the unitThe research unit called "comportement et noyaux gris centraux" was firstly certified as University Research Unit (URU) and thereafter, as EA4712 in 2012 at the University of Rennes 1. It follows the creation of the deep brain stimulation center at the university medical center of Rennes in 2006.

1 N4:2

 1 Permanent researchers from Institutions and similar positions N3: Other permanent staff (technicians and administrative personnel) 1 Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (technicians and administrative personnel) spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) obtained during the period 2 Overall assessment of the interdisciplinary unit Introduction The research topics of the EA4712 unit mainly concern the role of the basal ganglia in the control of behaviour (action, emotion and motivation) through the model of deep brain stimulation in neurological and psychiatric disorders. The unit emerged in 2006 with the creation by Mr Marc VÉRIN of the deep brain stimulation center at the university medical center of Rennes. It was certified as a research unit in 2012. It is thus a relatively young unit whose perimeter is being consolidated. The strategy for the next five years is ambitious and mainly aims to broaden and deepen the key themes of the unit. The goal is to join an INSERM unit at the end of the contract.

signed by their chairman." (Article 8, paragraph 5) 2 The evaluation reports "are signed by the chairman of the expert committee". (Article 11, paragraph 2)

Strengths and opportunities in the context

The strengths of the unit are: interdisciplinarity, attractiveness and originality of the main theme. Moreover, the unit can rely on a good regional scientific ecosystem (INSERM, CNRS, INRIA, and IRISA).

The opportunities are real (partnerships with the industry, international collaborations) and will allow to reinforce and extend multidisciplinarity.

Weaknesses and threats in the context

The weaknesses are the lack of an EPST label and consequently the lack of permanent researchers from institutions, the lack of permanent professors from non-medical university departments, the lack of methodological support to develop multimodal neuroimaging and a dispersion of the themes.

The main threat comes from competition with other neuroscience teams at the national and international level.

Recommendations

The committee strongly recommends that the team consider from now on a consolidation or even an integration with other local units (in particular, U746 VISAGES) to benefit from a better administrative and scientific environment. This will help obtaining an EPST label and provide better opportunities for the future.