Vanessa Prévot

Cédric Gastaldi

Claude Forano

Pickering emulsions based on layered double hydroxides and metal hydroxides

Keywords: Layered double hydroxides, hydroxides salt, Pickering emulsion, stabilization, Pickering emulsion polymerization

As previously underlined in this book, Pickering emulsions have in recent years gained increasing attention due to their interesting properties related to the replacement of surfactants by solid microparticles or nanoparticles. Such change in the nature of the stabilizer confers higher stability and lower toxicity to the emulsions. This chapter focus on the recent advances in the specific use of a peculiar class of inorganic bidimensionnal particles the Layered Double Hydroxides (LDH) and hydroxides salts in Pickering emulsion process. The properties of the two main classes of LDH involved in the stabilization of emulsion that is pristine materials and modified LDH with organic anions, are described.

Then the different results obtained for oil-in-water, water-in-oil and water-in-water involving LDH or hydroxides salt particles are discussed. At last, the interest of Pickering emulsion stabilized by LDH in various applications are also reviewed.

1-Introduction

In the past two decades, there has been an increasing interest in the development of Pickering emulsion systems for various applications. As described in the pioneer works of Ramdsen [START_REF] Ramsden | Separation of solids in the surface-layers of solutions and suspensions (observations on surface-membranes, bubbles, emulsions, and mechanical coagulation). Preliminary account[END_REF] and Pickering [START_REF] Pickering | CXCVI.-Emulsions[END_REF], solid particles can adsorb at the liquid interface upon partial wetting of the particle surface avoiding droplet coalescence and conferring stability to the emulsion. Some of the reported benefits of inorganic particles instead of surfactant to stabilize emulsions are a higher stability, functionality and a lower toxicity especially in terms of irritancy and cytotoxicity. Many factors influence the properties of Pickering emulsion, including particle size, wettability (often expressed as a contact angle θ at the three-phase boundary), initial location, and 63interparticle interactions. Comprehensive chapters are provided in the first part of this book on formation, stability and applications of Pickering emulsion and reviews have already been published [START_REF] Chevalier | Emulsions stabilized with solid nanoparticles: Pickering emulsions[END_REF][START_REF] Gonzalez Ortiz | Current Trends in Pickering Emulsions: Particle Morphology and Applications[END_REF][START_REF] Lu | Recent progress in nanoclay-based Pickering emulsion and applications[END_REF][START_REF] Machado | Effect of adding a third polysaccharide on the adsorption of protein microgels at the interface of polysaccharide-based water in water emulsions[END_REF] in particular by Binks [START_REF] Binks | Particles as surfactants-similarities and differences[END_REF] and Aveyard et al. [START_REF] Aveyard | Emulsions stabilised solely by colloidal particles[END_REF].

According to a recent review, [START_REF] Gonzalez Ortiz | Current Trends in Pickering Emulsions: Particle Morphology and Applications[END_REF]) various solid particles with different chemical compositions and morphologies can efficiently be involved in emulsion stabilization, ranging from spherical shape ( SiO 2 , TiO 2 , Fe 2 O 3 , polystyrene (PS) latexes), to 2D structures ( graphene oxides, hexagonal boron nitride, graphitic carbon nitride, …), nanosheets (kaolinite, montmorillonite, illite, layered double hydroxides), disklike shape (Laponite®), nanotubes (carbone nanotubes, halloysite) to fibrous shape (sepiolite, zein particles). Their nature affects both the emulsion formation and their subsequent properties. Among all the inorganic particles used for Pickering emulsion stabilization, 2-D structure with platelet shape such as clay minerals have properties leading to plates lying flat at the interface and more strongly held compared to spherical particles.

Compared with the well-established use of 2D particles from the smectite group such as montmorillonite, kaolinite and Laponite®, preparing Pickering emulsion in presence of layered double hydroxides (LDH) has only recently attracted attention due to the peculiar physical and chemical properties of LDH. [START_REF] Rives | Layered Double Hydroxides: Present and Future[END_REF][START_REF] Duan | Structure and bonding : Layered Double Hydroxides[END_REF][START_REF] Forano | Layered Double Hydroxides[END_REF] The structure of LDH is related to that of brucite, Mg(OH) 2 in which a portion of the Mg 2+ has been replaced by Al 3+ . Anions along with water, are intercalated between the layers to maintain electroneutrality. Based on a combination of a large variety of divalent and trivalent metal cations, the general formula for the LDH family can be written as (M II 1-x M III x (OH) 2 )(A m- x/m nH 2 O) where (M II 1-x M III x (OH) 2 ) represents the layer, and (A m-

x/m nH 2 O) represents the interlayer species. Contrary to clay minerals, LDH are naturally rare, however they can be easily prepared in a large quantity and organically modified. According to the synthetic method and parameters used, LDH particles size can be tuned over a large range with lateral dimensions ranging from 30 nm (Xu, Stevenson et al. 2006, Xu, Stevenson et al. 2006[START_REF] Gunawan | Direct Assembly of Anisotropic Layered Double Hydroxide (LDH) Nanocrystals on Spherical Template for Fabrication of Drug-LDH Hollow Nanospheres[END_REF] to more than 5 m [START_REF] Okamoto | Factors affecting the crystal size of the MgAl-LDH (layered double hydroxide) prepared by using ammonia-releasing reagents[END_REF]) and thicknesses from 1 nm to 20 nm. It should be underlined the most of the reported synthetic LDH lead to high level of intergrowth of the platelets and secondary aggregation of several micrometres.

Even if LDH display many interesting features such as wide-ranging chemical compositions, variable layer charge densities, ion-exchange properties, reactive interlayer spaces and hydroxylated surfaces, their colloidal stability is difficult to control mainly due to the high charge density of the layers avoiding spontaneous swelling in water.

The present review chapter intends to present the current-state of the art in the Pickering emulsion stabilized by LDH particles. Special attention will be paid to the properties of the LDH particles involved in these emulsion and the interactions at the nanoscale level, since these are crucial for the stability of the final Pickering emulsion. Three main categories of Pickering emulsions will be distinguished: water-in-oil, oil-in-water and water-in-water with a focus of the nature of the LDH particles involved in term of hydrophilicity and hydrophobicity. Finally, the last part is devoted to the use of the LDH Pickering emulsions in applications, particularly for adsorption, catalysis and to produce nanocomposite colloids with enhanced properties. This chapter concludes with some perspectives for future research in the field of LDH-based Pickering emulsions.

2-LDH and LH stabilizing particles used for Pickering emulsions

Common LDH containing simple inorganic anions such as CO 3 2-, Cl -, NO 3 -, SO 4 2-display layers with high charge density due to structural constraints. Indeed, LDH with chemical formula

[M II 1-x M III x (OH) 2 ][X q-
x/q .nH 2 O] for which most encountered x values range from 1/5 to 1/3, develop layer charge densities (LCD) in between 2.5 to 4.2 positive charge per nm 2 ; LCD values that are far higher than those shown by other 2D ion exchangers (smectite, titanate).

These intrinsic charge properties lead to robust layer/interlayer interactions and a very strong hydrophilic character, properties that may limit exfoliation and solvent dispersion.

Because the formation of LDH-based stable Pickering emulsions needs to overcome LDH inter-particles interactions and favor interactions at liquid-liquid interfaces, it is recommended not only to control the size of the LDH particles but also to chemically tune their surface properties (anionic species, charge density, hydrophilic lipophilic balance (HLB), wettability). It is well established that amphiphilic molecules are used to stabilize oil in water emulsions as they reduce the surface tension at the liquid-liquid interface. Many of these surfactants, preferentially anionic and non-ionic surfactant, may undergo surface adsorption or bulk intercalation by LDH, then rendering them lipophilic. Some of these amphiphilic molecules have been used as co-emulsifiers or chemical modifiers of LDH for Pickering emulsion stabilization. Few organic molecules were tested yet: an anionic surfactant (dodecyl sulfate) [START_REF] Wang | Double Phase Inversion of Emulsions Containing Layered Double Hydroxide Particles Induced by Adsorption of Sodium Dodecyl Sulfate[END_REF], a short amphiphilic molecule (glutamate) [START_REF] Li | Alkyl Ketene Dimer Emulsions Stabilized by Layered Double Hydroxide Particles Modified with Glutamic Acid[END_REF], a dye molecule (Methyl orange) [START_REF] Li | Roles of methyl orange in preparation of emulsions stabilized by layered double hydroxide particles[END_REF] and two polymer Tween 80 [START_REF] Kura | Preparation of Tween 80-Zn/Al-Levodopa-Layered Double Hydroxides Nanocomposite for Drug Delivery System[END_REF] and Span 80 [START_REF] Wang | Pickering Emulsions Stabilized by a Lipophilic Surfactant and Hydrophilic Platelike Particles[END_REF].

Sodium Dodecyl sulfate (SDS) (C 12 H 25 SO 4 Na), one of the most used surfactant in emulsion formation, is also the amphiphilic anion (DS) that has been most combined with LDH for many applications. Adsorption of DS on the LDH layer surface leads to a dense epitaxial packing of anions, the -O-SO 3 -groups attached to the positive layers with the hydrophobic tails orientated far away from the bulk, then reversing the zeta potential from positive values, usually +30/+40 mV, to neutral or negative values depending on pH. This surface modification lowers the wettability of the LDH platelets favoring the interaction with oil phase.

Many papers report the adsorption and the intercalation of Methyl orange by LDH, mainly for purpose of depollution. Tween-80 and Span-80 are non-ionic surfactants, derived from the condensation of oleic acid and polyethoxylated sorbitan or sorbitol molecules, respectively, with different HLB value of 15 and 4.3. They aid in minimizing the interfacial tension of the W/O primary emulsion and stabilize oil in water droplets of 12 m size. Few papers [START_REF] Wang | Pickering Emulsions Stabilized by a Lipophilic Surfactant and Hydrophilic Platelike Particles[END_REF][START_REF] Kura | Preparation of Tween 80-Zn/Al-Levodopa-Layered Double Hydroxides Nanocomposite for Drug Delivery System[END_REF]) reported that Tween-80, and Span-80, may adsorb to the LDH surface through their polar part. Such coating preserves the structure while changing their wettability.

Fluorescent confocal laser scanning microscopy analysis is the common technique used for imaging nanoparticles in Pickering emulsions at the liquid-liquid interface. Thanks to their anion exchange properties and hydrophilic properties, LDH are able to intercalate or adsorb anionic fluorescent probes for imaging [START_REF] Yan | A Novel Type of Aqueous Dispersible Ultrathin-Layered Double Hydroxide Nanosheets for in Vivo Bioimaging and Drug Delivery[END_REF][START_REF] Ma | Restriction-Induced Luminescence Enhancement in 2D Interlayer Supramolecular Infinite Solid Solution for Cell Imaging[END_REF]). For such application, LDH were functionalized mainly with Rhodamine B and Fluorescein [START_REF] Musumeci | Fluorescent layered double hydroxide nanoparticles for biological studies[END_REF][START_REF] Legentil | Revisiting fluorescein and layered double hydroxide using a synergistic approach: A complete optical study[END_REF]) (Fig. 1). [START_REF] Legentil | Revisiting fluorescein and layered double hydroxide using a synergistic approach: A complete optical study[END_REF]. Copyright 2019 Elsevier.

3-Pickering emulsion involving LDH and LSH particles

Oil in water emulsions

As described above, the unique properties of LDH such as a variable anion exchange capacity allowing tunable surface properties and hydrophile/lipophile balance (HLB), added to a 2D morphology, with controlled platelet size and aggregation, make them prime candidates for the preparation of stable emulsions for various applications [START_REF] Machado | Layered clay minerals, synthetic layered double hydroxides and hydroxide salts applied as pickering emulsifiers[END_REF]). However, since the pioneering works of G. Lagaly and S. Abend [START_REF] Abend | Bentonite and double hydroxides as emulsifying agents[END_REF] that reported in the early 2001 the interest to use LDH to stabilize o/w emulsions, surprisingly there has been very few studies on LDH-based Pickering emulsions (Table 1). o/w emulsions stabilized by LDHs were more investigated than w/o emulsions in agreement with the hydrophilicity of the LDH particles. In most of the studies reported in the literature, LDHs are never used alone but they are either surface modified or used with a co-emulsifier because due to their hydrophilic properties, LDH particles preferentially favor the formation of o/w emulsions. Pure LDHs display attachment [START_REF] Aveyard | Emulsions stabilised solely by colloidal particles[END_REF] energy too low to prevent emulsion coalescence. In addition, reversible o/ww/o process was described for few LDH systems [START_REF] Zhang | Influence of emulsification process on the properties of Pickering emulsions stabilized by layered double hydroxide particles[END_REF]. Chemical composition of LDH investigated was limited to Mg R Al (with R = 2 and 3) probably due to the ease to prepare colloidal solutions for this chemical composition. 1:99 [START_REF] Cui | Facile preparation of grass-like structured NiCo-LDH/PVDF composite membrane for efficient oil-water emulsion separation[END_REF] Among the key factors ruling out the particle adsorption at the o/w interface, surface charge density has an important role. It favors not only the steric hindrance that impedes droplet coalescence but also the attachment of particles to the interface, although the mechanism still needs to be clarified. Changing the M 2+ /M 3+ molar ratio in LDH is a way to control the zeta potential and the electrostatic forces with the interface. An additional strategy consists to add salts in the LDH colloidal solutions. Two papers [START_REF] Yang | Pickering emulsions stabilized solely by layered double hydroxides particles: The effect of salt on emulsion formation and stability[END_REF][START_REF] Yang | Effect of dispersion pH on the formation and stability of Pickering emulsions stabilized by layered double hydroxides particles[END_REF]) report the effect of NaCl salt addition on o/w emulsion stabilization by LDS, namely Mg 2 Al-Cl. Due to both the positive charge and the high charge density of the layers, LDH display high zeta potential values (+30 -+40 mV). Zeta potential has a crucial role on the dispersion state of particle suspensions Such positive electrochemical field favors LDH platelets repulsion and prevents particle aggregation leading to stable colloidal solutions. As it controls the particle wettability, it may also help to the attachment of the LDH platelets at the o/w interface that displays intrinsically a negative charge due to the local concentration of OH -ions. However, salt addition is needed to reduce the interface charge potential, in order to overcome the energy barrier for LDH adsorption and stabilize the emulsion. A reduction of the zeta potential is also necessary to better control the LDH-LDH repulsions and favor their concentration at the o/w interface. Addition of salt is a key factor as it affects both the potential of o/w interface but also it impacts the LDH zeta potential. Indeed, as already mentioned by Lagaly et al. [START_REF] Abend | Bentonite and double hydroxides as emulsifying agents[END_REF], and confirms by Yang Fei et al. [START_REF] Yang | Pickering emulsions stabilized solely by layered double hydroxides particles: The effect of salt on emulsion formation and stability[END_REF][START_REF] Yang | Effect of dispersion pH on the formation and stability of Pickering emulsions stabilized by layered double hydroxides particles[END_REF], the  value of Mg 2 Al-Cl decreases under addition of increasing NaCl concentrations. As suggested by these authors, increasing the ionic strength leads to a contraction of the Stern layer of the diffuse electrical double layer, modifies the surface charge and decreases . It may be note that the transition between sol and gel phases of the LDH suspensions occurs at concentration between 0.2 to 1 M, depending on the LDH weight % (respectively from 4.0% to 0.5%). Increasing NaCl concentration favors flocculation and LDH particle attachment at the o/w interface.

Consequently, adsorption of Mg 2 Al-Cl platelets at the o/w interface were found to be optimal for NaCl concentrations in between 0.1 and 1M whatever the LDH wt% and emulsions were stable for 3 months. In such NaCl concentration range, drop sizes vary from 50 m to 10 m when LDH wt% is increased from 0.5 to 4% respectively. Increase in pH has a similar effect [START_REF] Yang | Effect of dispersion pH on the formation and stability of Pickering emulsions stabilized by layered double hydroxides particles[END_REF] In another hand, stable Pickering o/w emulsion may be prepared by tailoring the wettability of the particles by surface modification with lipophilic molecules. Adsorption of ionic and non-ionic surfactants, or polyelectrolytes at the particle surface allows to control the Hydrophilic Lipophilic Balance (HBL) of the emulsifier, a key parameter for emulsion stabilization [START_REF] Binks | Particles as surfactants-similarities and differences[END_REF]. Short amphiphilic molecules such as low molecular weight organic carboxylic acid, have also been used in combination with hydrophilic metal oxides nanoparticles for the preparation of stable o/w emulsions [START_REF] Akartuna | Stabilization of Oil-in-Water Emulsions by Colloidal Particles Modified with Short Amphiphiles[END_REF].

Following this approach, LDH in-situ modified by glutamic acid was used to stabilize oil in water emulsion for application in papermaking sizing process [START_REF] Li | Alkyl Ketene Dimer Emulsions Stabilized by Layered Double Hydroxide Particles Modified with Glutamic Acid[END_REF]

Water in water emulsions

Water-in-water (w:w) emulsions are obtained by mixing two water-soluble but mutually incompatible macromolecules in solution. This kind of emulsions is commonly found in a variety of food products. These systems have been known for a long time and been described many years ago [START_REF] Beijerinck | Ueber Emulsionsbildung bei der Vermischung wässeriger Lösungen gewisser gelatinierender Kolloide[END_REF]. The behavior of a mixture of two hydrophilic polymers is now well documented and numerous papers and reviews have been published [START_REF] Esquena | Water-in-water (W/W) emulsions[END_REF][START_REF] Nicolai | Particle stabilized water in water emulsions[END_REF][START_REF] Dickinson | Particle-based stabilization of water-in-water emulsions containing mixed biopolymers[END_REF]. Water-in-water emulsions arise from different combinations of macromolecular compounds that interact attractively or repulsively with each other leading to water-water phase separation. Attractiveness creates structured regions in the medium through complexation, aggregation and coacervation mechanisms, forming a polymer-rich phase in and a polymer-depleted phase. Such a phenomenon is called associative separation. On the other hand, repulsiveness generates different regions containing predominantly one of the polymer involved. The latter is the most commonly found. [START_REF] Piculell | Association and segregation in aqueous polymer/polymer, polymer/surfactant, and surfactant/surfactant mixtures: similarities and differences[END_REF][START_REF] Grinberg | Thermodynamic incompatibility of proteins and polysaccharides in solutions[END_REF][START_REF] Matalanis | Structured biopolymer-based delivery systems for encapsulation, protection, and release of lipophilic compounds[END_REF]) At low polymer concentration, a competition between the entropy of mixing and enthalpy is responsible for the co-solubility. However, when increasing the polymer concentration, a two-phase system is formed as the enthalpy prevails. This behavior is found in numerous aqueous polymer solutions. As an example, mixtures of polysaccharides of close chemical nature, such as dextran and pullulan, separate Some factors can influence the interactions between two incompatible polymers, among then, the pH and ionic strength, if at least one of the polymer involved in the system is charged. In this case, salts can play an important role by shielding the charges. Finally, temperature can also play a role by modifying the phase diagram changing the quality of the solvent. [START_REF] Vis | Donnan Potentials in Aqueous Phase-Separated Polymer Mixtures[END_REF] Even though w/w emulsions have been studied for many years, these systems are less known than their o/w and w/o counterparts principally due to increase in complexity. The first obvious difference is the presence of a single solvent which means that the two phases possess similar physical properties. These similarities between the phases lead to a slower rate of creaming compared to O/W droplets of the same size. This also leads to an extremely low interfacial tension and microstructures more sensitive to stirring, shaking and other external flow fields. But it also means that it is almost impossible to stabilize the droplets with surfactants. Stable water-in-water emulsions are still possible by gelation of the continuous phase, thus preventing the coalescence. Due to the fragility of the droplets, with gelation, deformed anisotropic droplets are stabilised. [START_REF] Nguyen | pH-Responsive Water-in-Water Pickering Emulsions[END_REF] Consequently, the major differences with o/w or w/o emulsions comes from the fact that w/w emulsions display a large interfacial thickness and a low surface tension, and consequently a low adsorption energy, that cannot be overcome by the addition of small amphiphilic emulsifiers. Large uniform colloids or particles over hundredths of nanometers are required to stabilize such fragile systems.

During the last 15 years, it has been observed that particles added to w/w emulsions such as two incompatible polysaccharides tend to accumulate at the water-water interface which lead to an increase of the stability of the emulsion by slowing down its coarsening. Since then, various kinds of nano and microparticles have been studied to stabilize w/w emulsions for food applications. [START_REF] Murray | Whey protein microgel particles as stabilizers of waxy corn starch + locust bean gum water-in-water emulsions[END_REF][START_REF] Peddireddy | Stabilization of Water-in-Water Emulsions by Nanorods[END_REF][START_REF] Gonzalez-Jordan | Enhancement of the particle stabilization of water-in-water emulsions by modulating the phase preference of the particles[END_REF][START_REF] Laranjo | Stabilization of gelatin and carboxymethylcellulose water-in-water emulsion by addition of whey protein[END_REF] Almost all of the particles tested are of organic origins. Among them we can cite carboxylated latex particules (Gonzalez-Jordan, Nicolai et al. 2018), or cellulose nanocrystals [START_REF] Peddireddy | Stabilization of Water-in-Water Emulsions by Nanorods[END_REF][START_REF] Ben Ayed | Water-In-Water Emulsion Gels Stabilized by Cellulose Nanocrystals[END_REF]) used in a PEO/Dextran system, β-lactoglobulin microgels in Xyloglucan/Amylopectin [START_REF] Machado | Effect of adding a third polysaccharide on the adsorption of protein microgels at the interface of polysaccharide-based water in water emulsions[END_REF]) system or zein particules, a protein from corn, in Gelatin/Dextran [START_REF] Chatsisvili | Colloidal zein particles at waterwater interfaces[END_REF]). However, really few inorganics [START_REF] Vis | Waterin-Water Emulsions Stabilized by Nanoplates[END_REF] were tested but the use of LDH has not yet been investigated despite their use for o/w emulsions.

Silica nanoparticles (SiO 2 NP) are interesting candidates for the preparation of Pickering emulsions because both particle size and surface properties can be easily controlled respectively by tuning Sol-Gel process conditions and surface functionalization. Consequently, SiO 2 NP were successfully used for the preparation of o/w and w/o emulsions. In order to face the difficult problem to stabilize w/w emulsions through the mandatory enhancement of interfacial attachment energy, functionalization of SiO 2 surface may be an appropriate strategy to tailor the hydrophile/lipophile balance and the wettability of SiO 2 NP. In 2018 Griffith et al.

(Griffith and Daigle 2018) functionalized, through an easy sol-gel condensation process, SiO 2 NP surface with 2-(methoxy(polyethyleneoxy)6-9propyl)trimethoxysilane. The organically modified particles were tested as an emulsifier for the stabilization of w:w emulsion made of polyethylene glycol and magnesium sulfate. They observed that droplet stability was related to the size of the silica particles used, achieving better stability with 50 nm particles than with 6 nm particles. The larger the particles, the greater the attachment energy.

Nevertheless, they obtained a stable emulsion using 6 wt% particles for up to seven days (regardless of particle size).

Ganley et al. [START_REF] Ganley | Stabilisation of water-in-water emulsions by montmorillonite platelets[END_REF]) investigated the stabilizing effects of montmorillonite platelets for a Polyethylene oxide(PEO)/Pullulan system. The PEO adsorbed strongly on the clay mineral platelets, thus favoring the formation of pullulan droplets in PEO. The droplets obtained were stable to both creaming and coalescence for at least 21 days.

In 2015, Vis et al. 18 studied the behavior of Al(OH) 3 (gibbsite), a 2D inorganic structure not far from the LDH structure, at the interface of w/w emulsions formed by mixtures of gelatin and dextran. Gibbsite platelets display anisotropic shape with lateral size ranging from 85 nm to 170 nm and a thickness of about 7 nm leading to a high aspect ratio (0.08-0.04).

Theoretical calculations 18 concluded that such bidimensional particles display a higher free We recently studied the effect of LDH, more specially, nanoplatelets of Mg 3 Al of around 100 nm, for the stabilization of three different emulsions systems (data not published). PEO droplets in Dextran, Dextran droplets in PEO and finally Gelatin droplets in Dextran.

For each system, it has been noted that up to 1% wt of LDH, the droplets were more numerous and of smaller size (Fig. 7). Functionalization of LDHs by fluorescein isothiocyanate-dextran (FITC-Dextran) allows to show that LDH nanoparticles may adsorb at the w/w interface while leading to a strong aggregation between droplets. These emulsions could resist in solution for over a week.

4-1 LDH preparation

Pre-formed LDH particles stabilizing emulsion, it is not the only way to associate emulsions and LDH. Indeed, the synthesis of LDH nanoparticles can be quite challenging, specially the fine control of the particles size. An alternative method has been developed using double hydrophilic block copolymers (DHBC) and pickering emulsions. In this method, the DHBC acts as both, growth control and stabilizing agents. For example, as shown by recently extended to synthetize a Cu-Al LDH phase with an efficient control of the size of the nano particles [START_REF] Layrac | Comprehensive study of the formation of stable colloids of CuAl layered double hydroxide assisted by double hydrophilic block copolymers[END_REF]).

4-2 Catalysis

As Pickering emulsions are versatile systems, their ability to be used in catalytic reactions has emerged as a promising and recent research field. [START_REF] Rodriguez | Catalysis in Pickering emulsions[END_REF] Multifunctional particles or modified particles can be involved in the stabilization process and then participate in the catalytic process leading to interesting selectivity and conversion. showing a high catalytic conversion.

4-2 Porous LDH materials

Pickering emulsions have been described as an efficient soft template approach to generate a porous structure. [START_REF] Zhu | Preparation of porous adsorbent via Pickering emulsion template for water treatment: A review[END_REF]. For instance, Li et al. [START_REF] Li | Roles of methyl orange in preparation of emulsions stabilized by layered double hydroxide particles[END_REF] reported from Pickering emulsion stabilized by methyl orange (MO) modified LDH particles

5-Conclusions

The few reported papers on Pickering emulsions stabilized by Layered double hydroxides have demonstrated that these 2D materials are suitable candidates for emulsion preparation. Indeed, LDH display easy tunable physico-chemical properties in term of charge density, surface functionalization, particle size and shape, wettability and hydrophilic lipophilic balance that may adapt to the thermodynamic control of the liquid-liquid interface. Already LDH modify by salts, amphiphilic molecules and polyelectrolytes have demonstrated efficient stabilization of different water in oil emulsion systems. The important knowledge that has been acquired on the preparation of a large variety of LDH, hybrid LDH and polymer based LDH nanocomposites is a great asset to open new opportunities for the stabilization of new water in oil emulsion systems not only for applications in the fields of pharmaceutics, cosmetics or food but also for the design of novel systems of confinement or encapsulation interesting catalysis, photocatalysis, biocatalysis or nanomedicine.

More investigations are needed however to overcome the difficulties to stabilize water in water emulsions of great interest for the development of green and sustainable chemistry.

Fig. 1 :

 1 Fig. 1 : A) Excitation and emission spectra of rhodamine B (). B) Excitation and emission spectra of fluorescein and silica nanoparticles doped with rhodamine B 1g. B) Excitation and emission spectra of . C) Emission spectra at 20 °C with excitation at 450 nm of LDHfluorescein (0.05%) powder with deconvolution in three contributions. Reproduced with permission from ref[START_REF] Legentil | Revisiting fluorescein and layered double hydroxide using a synergistic approach: A complete optical study[END_REF]. Copyright 2019 Elsevier.

  , when the pH of Mg 2 Al-Cl suspension is increased from 9.25 to 12.0,  decreases from 40 to nearly 20 mV enhancing the stability of the emulsion and decreasing the oil drop size up to a stable gel-like state. The synthetic minerals Na,K-Shigaite, Na-Natroglaucocerinite, Na-Motukoreaite display layered structures ([M 2+ 6 Al 3+ 3 (OH) 18 ][Na(H 2 O) 6 (SO 4 ) 2 ] with respectively M 2+ = Mn 2+ , Zn 2+ , Mg 2+ that are related to the LDH structure with additional Na + or K + and SO 4 2-intercalated ions. Compared to classical LDH, the difference in surface composition corresponds to an enhanced anion exchange capacity and an excess of surface charged species. They can disperse easily in aqueous solutions as for LDH in solutions containing high concentrations of NaCl. Stable Pickering o/w emulsions stabilized with these 3 minerals were obtained (do Amaral, de Freitas et al. 2020, do Amaral, Wypych et al. 2021) for high oil fractions (> 0.74) and a critical coverage concentration of particles of 0.25 wt% (e = 0.54) after 14 days of storage as shown on Fig. 2 were Rhodamine-labelled K-shigaite particles are shown to adsorb at the o/w interface. Oil fraction increases with increasing particle concentration leading to a droplet size reduction. Stabilization of K + -shigaite-based Pickering emulsions was attributed to both partial reduction of interfacial energy with increasing shigaite particle content. That was confirmed by surface tension measurements and kinetic limitation due to steric hindrance to coalescence. Emulsion inversion from o/w to w/o occurs at high emulsion fraction, o > 0.5 and o > 0.75 for respectively oil fraction e < 0.20 and e > 0.15.

Figure 2 :

 2 Figure 2: CLSM image of paraffin/water emulsions (Φo = 0.38) for 0.75 wt% K-shigaite particles after 24 h. Insert: Corresponding photograph of emulsion after 14 days. Reproduced with permission from ref (do Amaral, de Freitas et al. 2020). Copyright 2020 Elsevier.

  Laser confocal scanning microscopy (LCSM) is mostly use to image the particles adsorbed at the droplet surface. However, it needs to label particles with fluorescent probes. Rhodamine or Fluorescein are the most used fluorophore molecules with LDH. Wei Li et al. (Li, Zhao et al. 2013) reported the addition of methyl orange (MO) to the preparation of Mg 2 Al-NO 3 -based Pickering paraffin/water emulsions. Adsorption equilibrium of the methyl orange by Mg 2 Al-NO 3 platelets was reached for a pH 10.0 after 24h contact time (25°C). Zeta potential decreases from +45 mV to +32 mV with increasing MO concentration up to 10 mM. Adsorption of the amphiphilic molecule modified noticeably the wettability as evidenced by the change in contact angle from 29° to 42.5° for pure LDH and LDH-MO (10 mM), rendering the particles partially hydrophobic. The ability of LDH surface to structurally orientate the amphiphilic MO molecule perpendicular to the surface with the anionic group electrostatically attached to the layer exposing the hydrophobic part to the liquid phase is favorable for the stabilization of the o/w interface. Emulsion are stabilized with volume fractions up to 80% and droplet size reduction from 300 m to 25 m for pure and 10 mM MO modified LDH. The dye molecule was used at the same time as a co-emulsifier, tuning the wettability of LDH particles and as a fluorescent probe for LCSM imaging as shown in Fig.3.[START_REF] Li | Roles of methyl orange in preparation of emulsions stabilized by layered double hydroxide particles[END_REF] 3-2 Water in oil emulsionsThe role of surfactant as co-emulsifiers for the stabilization of Pickering emulsions is well known since the works of Binks et al.[START_REF] Binks | Rheological Behavior of Water-in-Oil Emulsions Stabilized by Hydrophobic Bentonite Particles[END_REF]. Addition of ionic (SDS)[START_REF] Wang | Double Phase Inversion of Emulsions Containing Layered Double Hydroxide Particles Induced by Adsorption of Sodium Dodecyl Sulfate[END_REF]) and non-ionic (Span80, Tween 80) surfactants to Mg 2 Al LDH-based Pickering emulsions has been studied. Addition of lipophilic emulsifier change the wettability of the particle and help to stabilize the emulsion.

Figure 3 :

 3 Figure 3 : LCSM images of o/w emulsion stabilized by 0.25 wt% LDH modified with 10 mM.Reproduced with permission from ref[START_REF] Li | Roles of methyl orange in preparation of emulsions stabilized by layered double hydroxide particles[END_REF]. Copyright 2013 Elsevier.

Figure 4 :

 4 Figure 4: CLSM images of simple (a) and bridged emulsion at 0.2% (w/v) (b) and 0.7% (w/v)

  if the concentration is high enough. Phase separation of a mixture of a neutral polymer and a polyelectrolyte is inhibited by the entropy of mixing of the counter-ions but is therefore enhanced by the addition of the salts.[START_REF] Grinberg | Thermodynamic incompatibility of proteins and polysaccharides in solutions[END_REF] Tolstoguzov 1997, Dickinson 2019) Only around 1% wt of polymers, amount depending of their molar mass and chemistry, are needed to generate the phase separation. Polymers with high molar masses require lower concentration to obtain a phase separation due to the lower entropy of mixing. Proteins and polysaccharides are most likely to undergo phase separation by segregation because their affinity for water is very different.[START_REF] Tuinier | Phase behavior of casein micelles/exocellular polysaccharide mixtures: Experiment and theory[END_REF] For w/w emulsions, usually, the internal phase of the dispersed droplet is made of the phase with the smaller volume fraction. Bicontinuous emulsions can be formed with 50:50 polymer ratio, placing the emulsion near the inversion point as shown in the thermodynamic phase diagram. Fig.5shows the diagram of w/w emulsions made with the water/gelatin/maltodextrin system. This diagram is composed of a curve (the bimodal curve) separating cosolubility (one phase) and phase separation (two phases). Another important curve shown on this figure is the spinodal curve representing the boundary between unstable and metastable systems. Tie-lines indicate the pairs of phases in thermodynamic equilibrium. This lines all merge at the critical point. Beyond this point, the two phases are totally miscible and only form a single phase.

Figure 5 :

 5 Figure 5 : Scheme of w/w emulsion formation in the gelatin/maltodextrin system Reproduced with permission from (Esquena 2016). Copyright 2016 Elsevier.

  energy of adsorption than spherical particles ΔG ads (platelet) = -(π/4)d γ(1 -|cos θ|) and should act as better stabilizers. Consequently, nanoplatelets orientate flat to the interface with a poor effect of contact angle (Fig. 6 a, b, c, g) unlike SiO 2 nanospheres.

Figure 6 .

 6 Figure 6. (a) Calculated adsorption energy of nanoplates (167 nm) at the water-water interface (γ = 4 μN/m). Platelet vs sphere contact angle effect on (b) adsorption area and (c)

Figure 7 :

 7 Figure 7: A) Images from optical microscopy of of w/w emulsions composed of 5% gelatin, 15% dextran and 1% Mg 3 Al LDH. B) and C) Fluorescent confocal laser scanning microscopy images of w/w emulsions composed of 10% gelatin, 10% dextran and 1% Mg 3 Al LDH.

  Layrac et al.[START_REF] Layrac | Highly Stable Layered Double Hydroxide Colloids: A Direct Aqueous Synthesis Route from Hybrid Polyion Complex Micelles[END_REF] for the formation of Mg-Al LDH, the metallic cations were first mixed with the copolymers thus forming micelles constituted of almost only Al 3+ by preferential complexation of the trivalent cations. Then, Al 3+ were transformed into aluminum hydroxide by hydroxylation allowing the incorporation of Mg 2+ into the micelle by further hydroxylation leading to the Mg-Al phase21. Such technique has been also

( 0 .

 0 Fig 8 SEM images of dried hollow colloidosomes obtained from o/w emulsion stabilized by 0.25 wt% LDH modified with 10 mM. Reproduced with permission from ref (Li, Zhao et al. 2013). Copyright 2013 Elsevier.

Table 1 :

 1 Reported studies on LDH-based Pickering emulsions

LDH Oil phase Co-emulsifiers / Additives Emulsification conditions Ref.

	Mg 2 Al-NO 3	Paraffin oil	Bentonites	Bentonite:LDH wt:	(Abend and Lagaly 2001)
			(Wyoming;	1:1;1:2
			Ordu)	LDH+Bentonite : 0.3-3
			Montmorillonit	wt%
			e-Na	o/w : 0.38/0.62
	Mg 3 Al-CO 3	Paraffin oil	NaCl	LDH: 0.5-4 wt% /	(Yang, Liu et al. 2006)
		(C 16 -C 26		NaCl: 10 -3 -2M
		isoalkane)
	Mg 2 Al-Cl	Paraffin oil	NaCl	LDH: 0.5-2 wt% /	(Yang, Niu et al. 2007)
		(C 16 -C 26		NaCl: 10 -4 M / o/w :
		isoalkane)		0.5/0.5/ pH 9-12.5
	Mg 2 Al-Cl	Paraffin oil	Sodium	LDH: 0.5-1.5 wt% /	(Wang, Yang et al. 2008)
		(C 16 -C 26	dodecylsulfate	SDS: 1-10 -1 M / o/w :
		isoalkane)	(SDS)	0.5/0.5
	Mg 2 Al-Cl	Paraffin oil	Sorbitan	LDH: 1 wt% / Span 80:	(Wang, Yang et al. 2010)
		(C 16 -C 26	monoleate	1-10 -1 M / o/w :
		isoalkane)	(Span 80)	0.5/0.5
	Mg 2 Al-NO 3	paraffin oil	Methyl orange	LDH: 0.25 wt% / MO:	(Li, Zhao et al. 2013)
		(C 16 -C 26	(MO)	0-10 -M / o/w : 0.1-
		isoalkane)		0.9/0.9-0.1
	Mg 3 Al-NO 3	Alkyl ketene	Glutamate	LDH:Glu 0-3mmol.g -1 /	(Li, Song et al. 2017)
	Mg 3 Al-	dimer wax		LDH: 0.25 wt% / MO:
	Glutamate	(AKD)		0-10 -M / o/w : 1/9
	Mn 2 Al-	Liquid		LDH: 0.01-0.75 wt% /	(do Amaral, de Freitas et
	SO 4 /K 2 SO4 (K-	paraffin		o/w : 0.18-0.74/9	al. 2020)
	Shigaite)
	Mn 2 Al-
	SO 4 /K 2 SO4 (Na-
	Shigaite) Zn 2 Al-

  LDH particles at the surface of the oil droplets and the formation of a stable steric shell that inhibits the droplet coalescence. It must be note that unlike, what authors claimed, glutamate was not intercalated in the Mg 3 Al-NO 3 structure but only adsorbed at the surface which was sufficient enough for emulsion stabilization. Indeed, a short basal spacing value of 0.863 nm measured for Mg 2 Al-Glutamate cannot account for glutamate intercalation as reported recently by Wei Wu et al.[START_REF] Wu | Synthesis of glutamate intercalated Mg-Al layered double hydroxides: influence of stirring and aging time[END_REF]).

	. The oil
	used was a wax oil made of alkyl ketene dimer (AKD). The use of organophilic molecules such
	as glutamate, a zwitterion with short hydrophobic chain and moderate wettability is an
	alternative to long chain surfactant that may causes an unfavorable increase in emulsion
	viscosity, therefore requiring lower O/W ratio and much energy. Glutamate-modified LDHs
	was efficient to stabilize AKD/w emulsions. Emulsion volume fraction of 100% was obtained

for glutamate concentration greater than 1.5 mmol/g after 24h and stable over more than glutamate-modified

  adsorption energy. CLSM images of dextran (9% )/gelatin(3%) emulsion stabilized by gibbsite platelets (d) 0.4 wt% and (e) 1 wt%. (f) Gibbsite plates (700 nm) at the surface of a dextranrich droplet. (d) Gelatin-rich droplet in a dextran-rich continuous phase on a gibbsitecovered glass substrate with permission of ref. 18.

	Stable w/w emulsions were obtained for 0.4 w% gibbsite particles content, 1 wt% was
	needed for a full coverage of the droplets (Fig 6 d,e f). No coalescence neither sedimentation
	was observed after 3 weeks. This effect was explained by the fact that the gibbsite
	nanoplatelets were localized at the interface of the w/w emulsions aggregated with each
	other, thus forming a weak gel of droplets.
	This last example highlights the interest of 2D metal hydroxide nanoplatelets to stabilize
	w/w emulsions. LDH display similar hexagonal platelets to gibbsite and appear as good
	candidate for such application.

  Shan et al.[START_REF] Shan | Thermodynamically Stable Pickering Emulsion Configured with Carbon-Nanotube-Bridged Nanosheet-Shaped Layered Double Hydroxide for Selective Oxidation of Benzyl Alcohol[END_REF] reported a thermostable water/toluene Pickering emulsion involving LDH nanohybrid system combining Mg 2 Al-CO 3 LDH and carbon nanotube (CNT). A large emulsion volume fraction and small droplets size (30-150 m) were readily formed, producing high emulsion interfacial surface areas compared to LDH or CNT used alone as emulsifiers. The LDH-CNT Pickering emulsion remains stable over time at room temperature and more than 5h at 85°C. LDH-CNT modified with Ru particles were involved in Pickering emulsion and were then tested for the selective oxidation of benzyl alcohol to benzaldehyde,


Nizar Joher

Marie Matignon

Philippe Grimbert
email: philippe.grimbert@aphp.fr

Philippe Pr

Grimbert

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

Keywords: Anti-CD38, Daratumumab, HLA Desensitization, Humoral Response, Solid Organ Transplantation

The presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient's blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient's morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation.

Introduction

HLA sensitization and antibody-mediated rejection

Solid organ transplantation (SOT) has become the best therapeutic option for end-stage organ disease but faces two major issues: the limited transplant supply and the poor long-term transplants outcome which have not improved over the past 30 years [START_REF] Optn | Organ Procurement and Transplantation Network -OPTN[END_REF][START_REF]Agence de la biomédecine[END_REF][START_REF] Loupy | Antibody-Mediated Rejection of Solid-Organ Allografts[END_REF]. This observation is related to the occurrence of antibody-mediated rejection (ABMR) which remains the death-censored leading cause of transplant loss across all solid organ transplants [START_REF] Loupy | Antibody-Mediated Rejection of Solid-Organ Allografts[END_REF][START_REF] Valenzuela | Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies[END_REF]. ABMR is defined on the association of histologic lesions (microvascular inflammation), histologic evidence of alloantibodiesendothelium interaction (c4d staining) and circulating donor-specific antibodies mostly directed against human leucocyte antigens (HLA) [START_REF] Loupy | Antibody-Mediated Rejection of Solid-Organ Allografts[END_REF][START_REF] Valenzuela | Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies[END_REF][START_REF]The XIIIth Banff Conference on Allograft Pathology: The Banff 2015 Heart Meeting Report: Improving Antibody-Mediated Rejection Diagnostics: Strengths, Unmet Needs, and Future Directions[END_REF][START_REF] Schinstock | A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation -a cohort study[END_REF][START_REF] Roux | Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR)[END_REF][START_REF] Drachenberg | Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema[END_REF][START_REF] Demetris | Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection[END_REF][START_REF] Loupy | The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell-and antibody-mediated rejection[END_REF]. Following blood transfusion, pregnancy or previous graft failure, candidates for organ transplantation can become sensitized against HLA and produce circulating anti-HLA antibodies [START_REF] Zhang | Donor-Specific Antibodies in Kidney Transplant Recipients[END_REF][START_REF] Butler | Not All Antibodies Are Created Equal: Factors That Influence Antibody Mediated Rejection[END_REF]. In particular, pending on their properties donor-specific anti-HLA antibodies (DSA), are responsible for ABMR leading to allograft dysfunction and graft loss [START_REF] Lefaucheur | From Humoral Theory to Performant Risk Stratification in Kidney Transplantation[END_REF][START_REF] Lefaucheur | IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury[END_REF][START_REF] Loupy | Complement-binding anti-HLA antibodies and kidney-allograft survival[END_REF][START_REF] Montgomery | HLA in transplantation[END_REF][START_REF] Tinckam | Survival in sensitized lung transplant recipients with perioperative desensitization[END_REF][START_REF] Plazak | Clinical Outcomes of Perioperative Desensitization in Heart Transplant Recipients[END_REF]. Currently, immunomotoring of the transplant candidate's is routinely performed in order to stratify the immunological risk by determining the presence and specificity of anti-HLA antibodies and potential DSA [START_REF] Zhang | Donor-Specific Antibodies in Kidney Transplant Recipients[END_REF][START_REF] Montgomery | HLA in transplantation[END_REF]. The highly sensitized patients have longer waitlist times with significant adverse effect on both quality and quantity of life [START_REF] Optn | Organ Procurement and Transplantation Network -OPTN[END_REF][START_REF]Agence de la biomédecine[END_REF]. Several strategies are applied to limit the time on the waiting list of highly immunized patients such as prioritization in transplant's access, promotion of transplantation from living-donor allografts, development of kidney paired donation and desensitization.

Desensitization and solid organ transplantation's outcome

Current desensitization strategies have been developed in kidney transplantation and extended to other solid organ transplantation [START_REF] Tinckam | Survival in sensitized lung transplant recipients with perioperative desensitization[END_REF][START_REF] Plazak | Clinical Outcomes of Perioperative Desensitization in Heart Transplant Recipients[END_REF][START_REF] Bourassa-Blanchette | Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta-analysis -Part II: Non-kidney transplant[END_REF][START_REF] Shah | Desensitization in heart transplant recipients: Who, when, and how[END_REF][START_REF] Matsumoto | Donor-specific antibody and sensitized patients in intestinal transplantation[END_REF]. The goal of desensitization regimens in presensitized transplant candidates is twofold including the reduction of anti-HLA level to allow transplantation and the improvement of transplantation outcome through the prevention of ABMR [START_REF] Schinstock | Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: Is there still a role for desensitization?[END_REF]. A stepwise approach is commonly used to desensitize including, (i) either high-dose intravenous immunoglobulin (IVIG) or low dose IVIG in association with plasmapheresis to remove antibodies and, (ii) anti-CD20 targeting agent, such as rituximab, to prevent rebound antibodies development by B cell depletion [START_REF] Vo | Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients[END_REF][START_REF] Vo | Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation[END_REF][START_REF] Vo | Rituximab and intravenous immune globulin for desensitization during renal transplantation[END_REF][START_REF] Loupy | Combined posttransplant prophylactic IVIg/anti-CD 20/plasmapheresis in kidney recipients with preformed donor-specific antibodies: a pilot study[END_REF][START_REF] Jordan | Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients[END_REF]. Regarding the kidney transplantation field, despite the desensitizing effect, the subsequent transplantation is associated with higher rate of rejection and higher rate of hospital readmission after transplantation [START_REF] Amrouche | Longterm Outcomes of Kidney Transplantation in Patients With High Levels of Preformed DSA: The Necker High-Risk Transplant Program[END_REF][START_REF] Orandi | Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study[END_REF][START_REF] Motter | Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation[END_REF]. However, long term outcomes for patient and graft survival have been reported to be similar to that of non-sensitized patients [START_REF] Kahwaji | Six-year outcomes in broadly HLA-sensitized living donor transplant recipients desensitized with intravenous immunoglobulin and rituximab[END_REF]. Furthermore, the benefit of desensitization compared to remaining on the transplant waiting list has been evaluated only in few large studies and their results remain controversial [START_REF] Süsal | Transplantation: Desensitization and survival in kidney transplant recipients[END_REF][START_REF] Heidt | Transplantation in highly sensitized patients: challenges and recommendations[END_REF]. Montgomery et al. and Orandi et al. reported a survival benefit at five years after kidney transplantation in 211 and 1025 desensitized patients respectively compared to patients remaining on the waiting list [START_REF] Montgomery | Desensitization in HLA-incompatible kidney recipients and survival[END_REF][START_REF] Orandi | Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors[END_REF]. Interestingly, in a study performed on 213 desensitized recipients of living donor transplants, Manook et al. showed that desensitization was not associated with a survival benefit compared to matched sensitized control patients who were waitlisted [START_REF] Manook | Post-listing survival for highly sensitised patients on the UK kidney transplant waiting list: a matched cohort analysis[END_REF]. On the other hand, keeping patients a long time on dialysis represent a considerable financial burden while decreasing the quality and length of life for affected patients [START_REF] Süsal | Transplantation: Desensitization and survival in kidney transplant recipients[END_REF][START_REF] Heidt | Transplantation in highly sensitized patients: challenges and recommendations[END_REF].Thus, it appear as necessary to develop novel therapeutic approaches in order to prevent ABMR and improve long-term survival of transplanted organs in highly immunized recipient.

Desensitization regimens targeting plasma cells

The available therapeutic tools to manage the humoral response appears modestly successful in the context of SOT and alloimmunity. Indeed, antibody rebound due to plasma cells (PC), which do not express CD20, limit the efficacy of the most commonly used strategy combining IGIV, plasmapheresis and B cell depletion by anti-CD20 depleting agent. Targeting PC with new pharmacological tool from autoimmunity and cancer research could allow a better management of the humoral response in desensitization protocols [START_REF] Jordan | The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection[END_REF]. In the germinal center, after the enhancement of alloantigen responses by T follicular helper (Tfh), activated B cells develop into memory-B cells, progress to plasmablasts and ultimately to andibody-producing PC [START_REF] Leibler | Costimulatory blockade molecules and B-cell-mediated immune response: current knowledge and perspectives[END_REF][START_REF] Tangye | The good, the bad and the ugly -TFH cells in human health and disease[END_REF]. These PC are the longlived mediators of lasting humoral immunity and persist in medullary niche where they can secrete high-affinity complement-activating DSAs [START_REF] Leibler | Costimulatory blockade molecules and B-cell-mediated immune response: current knowledge and perspectives[END_REF][START_REF] Nutt | The generation of antibody-secreting plasma cells[END_REF]. Several emerging strategies aim to deplete PCs compartment in order to prevent ABMR [START_REF] Jordan | The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection[END_REF][START_REF] Kwun | Experimental modeling of desensitization: What have we learned about preventing AMR?[END_REF]. First, Interleukin 6 (IL-6) is a cytokine promoting Tfh and enhancing the progression of B cells to high-affinity antibodies producing PC [START_REF] Brynjolfsson | Long-Lived Plasma Cells in Mice and Men[END_REF]. Tocilizumab, a first-in-class humanized monoclonal antibody (mAb) with specificity for IL-6R, reduce inflammation within the allograft during ABMR in heart and kidney transplantation [START_REF] Jordan | Interleukin-6: An Important Mediator of Allograft Injury[END_REF] and induce circulating DSA reduction [START_REF] Choi | Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients[END_REF]. Clazakizumab is a humanized IgG1 mAb with specificity for IL6 which can also induce circulating DSA reduction [START_REF] Md Sj | Monoclonal) to Eliminate Donor Specific HLA Antibodies (DSAs) and Improve Transplant Rates in Highly-HLA Sensitized Patients Awaiting Renal Transplant[END_REF]. Both Tocilizumab and Clazakizumab are pharmacological agents with major interest in the development of desensitization strategies targeting PC [START_REF] Jordan | The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection[END_REF]46). On another hand, proteasome inhibitors represent one of the most promising solution to deplete PC in the setting of desensitization, targeting more selectively PCs population. Bortezomib and carfilzomib have been evaluated in desensitization trials, lacking control group, leading to controversial results [START_REF] Woodle | Prospective Iterative Trial of Proteasome Inhibitor-Based Desensitization[END_REF][START_REF] Tremblay | A prospective, iterative, adaptive trial of carfilzomib-based desensitization[END_REF]. Both induce significant PCs depletion whereas DSA level did not significantly decrease or rebound occurred rapidly. In fact, targeting PC may lead to rapid germinal center activation by deleting the negative feedback usually provided by PC and rebound humoral immunity and compensation [START_REF] Kwun | Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients[END_REF]. Therefore, dual targeting approach (combining PCs depletion with proteasome inhibitors and costimulation blockade) may silence the germinal center and prevent humoral compensation. This strategy has been recently evaluated using carfilzomib and belatacept as desensitization in highly sensitized non-human primate model with a reduction of bone marrow PC, DSA levels reduction, and prolongation of allograft survival. Most animals experienced ABMR with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response [START_REF] Ezekian | Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients[END_REF][START_REF] Schroder | Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model[END_REF]. An emerging therapy to induce DSA reduction and to prevent rebound DSA development is the use of antiplasma cell therapies such as anti-CD38, anti-CD19 or bispecific anti-CD3 / anti-BCMA (B cell maturation antigen). In this review, we propose to focus on anti-CD38 as a desensitization regimen in SOT.

CD38-Targeting strategies CD38 and CD38-targeting antibodies

The protein CD38 is a type II transmembrane glycoprotein known as a multifunctional molecule. CD38 play dual roles as receptors and ectoenzymes [START_REF] Quarona | CD38 and CD157: A long journey from activation markers to multifunctional molecules[END_REF]. The CD38/CD31 interactions are crucial to leukocyte adhesion and transmigration through the endothelium [START_REF] Dianzani | Lymphocyte adhesion to endothelium[END_REF]. CD38 is also an enzyme that catalyzes several reactions leading to the regulation of cytoplasmic calcium fluxes and a wide range of others physiological functions such as cellular metabolism [START_REF] Quarona | CD38 and CD157: A long journey from activation markers to multifunctional molecules[END_REF]. CD38, found throughout the immune system especially natural killer and PC, is highly expressed in multiple myeloma cells [START_REF] Van De Donk | CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance[END_REF]. Altogether, this has triggered the development of several CD38 antibodies to treat multiple myeloma [START_REF] Van De Donk | CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance[END_REF][START_REF] Van De Donk | CD38 antibodies in multiple myeloma: back to the future[END_REF][START_REF] Van De Donk | Multiple myeloma[END_REF]. Daratumumab (DARZALEX®, Janssen), fully human IgG1-kappa, was the first CD38 antibody that was recognized as an emerging therapy against myeloma in the last decade [START_REF] Lokhorst | Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma[END_REF]. Daratumumab have multiple effects including Fc-dependent immune-effector mechanisms and direct effects. The Fc-dependent immune-effector mechanisms include antibodydependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complementdependent cytotoxicity [START_REF] Van De Donk | CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance[END_REF][START_REF] Van De Donk | CD38 antibodies in multiple myeloma: back to the future[END_REF]. Direct effects include induction of apoptosis, as well as inhibition of CD38 ectoenzyme function, which may lead to disruption of the PCs niche. Those Fc-dependent effects and direct effects are associated with deep and sustained CD38 + cells depletion, mostly PC and NK cells [START_REF] Van De Donk | CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance[END_REF][START_REF] Van De Donk | CD38 antibodies in multiple myeloma: back to the future[END_REF][START_REF] Casneuf | Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma[END_REF]. The ability of daratumumab to efficacy deplete PCs compartment permit to use it as an new agent in therapeutic armamentarium for multiple myeloma [START_REF] Van De Donk | Multiple myeloma[END_REF]. Large clinical trials have demonstrated significant improvements in the outcome of patients with relapsed multiple myeloma with use of daratumumab and it has been recently approved in front-line regimens [START_REF] Van De Donk | Multiple myeloma[END_REF][START_REF] Lokhorst | Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma[END_REF][START_REF] Casneuf | Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma[END_REF][START_REF] Dimopoulos | Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma[END_REF][START_REF] Touzeau | Daratumumab for the treatment of multiple myeloma[END_REF]. Isatuximab (SARCLISA®, Sanofi) is a chimeric IgG1-kappa which has stronger direct effects than daratumumab but lower ability to induce Fc-dependent immune-effector mechanisms, while it remains unknown whether these functional differences observed between different CD38 antibodies affect their therapeutic utility [START_REF] Van De Donk | CD38 antibodies in multiple myeloma: back to the future[END_REF][START_REF] Van Bueren | Direct in Vitro Comparison of Daratumumab with Surrogate Analogs of CD38 Antibodies MOR03087, SAR650984 and Ab79[END_REF]. Many other strategies targeting CD38 are under development and a selection is listed in Table 1. The CD38-targeting antibodies generally represent a safe treatment. Indeed, the most reported toxicity is infusion related reactions which remain successfully controlled by premedication and infusion rate management with low frequency of recurrence during subsequent injections [START_REF] Radocha | Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma[END_REF]. A higher rate of viral infections in patients treated with daratumumab has been reported in some studies leading to a recommended administration of valaciclovir during the administration of anti-CD38 antibodies [START_REF] Radocha | Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma[END_REF].

Immunomodulatory effects of CD38-targeting antibodies

CD38-targeting antibodies have immunomodulatory effects such as improving the host-antitumor immune response [START_REF] Van De Donk | Immunomodulatory effects of CD38-targeting antibodies[END_REF]. Krejcik et al. showed that daratumumab monotherapy against myeloma was associated with both CD4+ and CD8+ T cell expansion [START_REF] Krejcik | Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma[END_REF]. This increase in T-helper cells and cytotoxic T-cell was associated with functional modification including elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor sequencing [START_REF] Van De Donk | Immunomodulatory effects of CD38-targeting antibodies[END_REF][START_REF] Krejcik | Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma[END_REF]. These modifications are associated with depletion of CD38 + immunosuppressive cells including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. It is well known that such regulatory cells inhibit the host-anti-tumor immune response in the context of several malignancies including multiple myeloma [START_REF] Zhang | Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu[END_REF][START_REF] Dwivedi | CD38 and Regulation of the Immune Response Cells in Cancer[END_REF][START_REF] Adams | High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action[END_REF]. Altogether, this immunomodulatory activity of CD38 antibodies may be essential to their therapeutic efficacy. Indeed, it has been highlighted in clinical trials showing that expansion of effector T-cells and eradication of immune suppressors cells by daratumumab used against refractory and newly diagnosed multiple myeloma was correlated to a marked improvement in response and progressionfree survival [START_REF] Lokhorst | Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma[END_REF][START_REF] Dimopoulos | Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma[END_REF][START_REF] Van De Donk | Immunomodulatory effects of CD38-targeting antibodies[END_REF][START_REF] Adams | High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action[END_REF]. It might be hypothesized that these immunomodulatory abilities have important implication for sustained control of the tumor and further deepening of response [START_REF] Van De Donk | Immunomodulatory effects of CD38-targeting antibodies[END_REF]. As a result of these pleiotropic immune modulation, CD38 antibodies also enhance anti-tumor activity of others anti-cancer drugs with several studies highlighting that CD38-targeting antibodies have strong synergistic activity, such as combination to lenalidomide as well as to PD1/PD-L1 inhibitors [START_REF] Van De Donk | Multiple myeloma[END_REF][START_REF] Chen | CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade[END_REF]. Besides effect on immune cells, CD38 antibodies may also modulate immunometabolic pathway. Indeed, CD38-targeting agent's exposure could lead to lower adenosine level in tumoral microenvironment, which is known as immunosuppressive metabolite [START_REF] Vijayan | Targeting immunosuppressive adenosine in cancer[END_REF][START_REF] Chatterjee | CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response[END_REF]. All these properties enhancing the anti-tumoral response are of major interest in the field of oncology while it could be problematic in immunosuppressive strategies such as autoimmune diseases treatment or desensitization and SOT's context.

CD38 antibodies in solid organ transplantation CD38 antibodies in non tumoral context

In the last decade, several strategies to handle with autoimmune or alloimmune pathologic situations include CD38 antibodies [START_REF] Zaninoni | The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease[END_REF][START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF][START_REF] Doberer | CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection[END_REF]. Indeed, long-lived plasma cells, which produce pathogenic antibodies, are unresponsive to standard immunosuppression. Besides PC depletion and immunomodulatory effect, CD38 expression on PCs from patients with autoimmune condition [START_REF] Cole | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus[END_REF] and reduction of auto-antibodies in patients exposed to daratumumab [START_REF] Frerichs | CD38-targeted therapy with daratumumab reduces autoantibody levels in multiple myeloma patients[END_REF] support the evaluation of daratumumab in patients with autoantibody-dependent disorders and, in extension, to alloimmune situation such as SOT. Available evidence about CD38 antibodies efficacy in these situations are mostly cases reports of daratumumab use against immune cytopenia. Daratumumab were used to treat warm autoimmune hemolytic anemia post-hematopoietic stem cell transplant [START_REF] Tolbert | Daratumumab Is Effective in the Treatment of Refractory Post-Transplant Autoimmune Hemolytic Anemia: A Pediatric Case Report[END_REF], refractory cold agglutinin disease [START_REF] Tomkins | Daratumumab for disabling cold agglutinin disease refractory to B-cell directed therapy[END_REF], Evans syndrome [START_REF] Blennerhassett | Post-allogeneic transplant Evans syndrome successfully treated with daratumumab[END_REF] and pure red cell aplasia [START_REF] Chapuy | Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation[END_REF] with improvement in the majority of cases. Regarding other autoimmune disease, the administration of daratumumab in two patients with refractory lupus was recently described exhibiting clinical responses associated with significant depletion of long-lived plasma cells and modulation of effector T-cell responses [START_REF] Ostendorf | Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus[END_REF]. As regard as autoimmune encephalitis, targeting CD38 was achieved with daratumumab in one case of life-threatening anti-NMDA receptor encephalitis and in one case of refractory anti-CASPR2 encephalitis with improvements of neurological sequelae [START_REF] Ratuszny | Case Report: Daratumumab in a Patient With Severe Refractory Anti-NMDA Receptor Encephalitis[END_REF][START_REF] Scheibe | Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis[END_REF]. In the last case, severe septicemia leading to patient death highlight an unmet need of rigorous clinical investigation to determine the efficacy and tolerance of CD38-targeting agent in autoimmune disease.

CD38 antibodies and ABMR treatment

In antibody-mediated non-neoplastic diseases, alloimmune situation such as SOT represent a field where targeting CD38 is promising. As alloantibody-producing PC express CD38 at a higher level than other CD38 + hematopoietic cells and CD38 antibodies induce a profound depletion of CD38 + PC, CD38 appears as a rational target to handle with harmful alloantibodies such as DSA [START_REF] Martin | Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab[END_REF][START_REF] Flores-Montero | Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma[END_REF]. Currently, only few studies have been published regarding the use of CD38 antibodies for desensitization in patients awaiting transplantation or for treatment of ABMR. Concerning treatment of ABMR, the first report was in a patient with refractory early active ABMR caused by anti-A isohemagglutinins after kidney transplantation from his ABO-incompatible sister [START_REF] Spica | Daratumumab for Treatment of Antibody-Mediated Rejection after ABO-Incompatible Kidney Transplantation[END_REF] . Based on the efficacy of daratumumab in the treatment of pure red cell aplasia following ABO-incompatible hematopoietic stem cell [START_REF] Chapuy | Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation[END_REF] and non-response of several therapies; daratumumab were tested as a rescue solution leading to a significant decrease of the pathogenic isohemagglutinins and resolution of tissue damage in the kidney biopsy. Kwun and colleagues also published a case report of daratumumab as a therapeutic strategy for refractory heart and kidney rejection in a patient who received heart and kidney transplants due to systemic lupus [START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF]. Both transplant biopsy showed T cell-mediated rejection, ABMR and diffuse PC infiltration associated to the presence of several DSA. To face refractory cardiogenic shock and acute kidney failure dependent to dialysis, a compassionate use of daratumumab lead to the resolution of both allograft function, improvement in acute kidney lesions with decreased PCs infiltrate and dramatic decline for the majority of DSA. A recurrent acute PC-rich rejection on kidney biopsy and significant ascension of DSA were successfully managed with daratumumab. Recently, two others cases were reported: one refractory ABMR after a heart transplant successfully treated with daratumumab and one chronic active ABMR in a kidney allograft recipient diagnosed with myeloma exposed to daratumumab [START_REF] Doberer | CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection[END_REF][START_REF] Aguilera Agudo | Daratumumab for Antibodymediated Rejection in Heart Transplant-A Novel Therapy: Successful Treatment of Antibodymediated Rejection[END_REF]. In the last one, the exhaustive immuno-monitoring showed that the main mode of action seems to be based on PC depletion, with profound PCs reduction in the bone marrow and peripheral blood and the abrogation of in vitro alloantibody production by PC enriched from bone marrow aspirates, leading to significant reduction in DSA levels [START_REF] Doberer | CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection[END_REF]. Another observation is that daratumumab led to depletion of NK cells infiltrating the allograft and circulating NK cells, which is major interest knowing the potential role of NK cells in microvasculature inflammation through engagement of their Fc gamma receptor IIIA with endothelium-bound DSA [START_REF] Parkes | Evidence for CD16a-Mediated NK Cell Stimulation in Antibody-Mediated Kidney Transplant Rejection[END_REF]. Interestingly, while follow up biopsy showed resolution of humoral activity, it was observed tubulointerstitial inflammation which prompted steroid treatment. The author highlighted that the molecular signature of this infiltrate was not similar to signature of T-cell mediated rejection leading to question the trigger of this infiltrate not associated with graft dysfunction. Indeed, daratumumab may trigger T-cell alloresponse, even if circulating regulatory T cells were not reduced in the patient's blood which is not necessarily correlated to the modification of immune cell populations at a tissue level. Moreover, the authors recently reported long term data of this case without evidence of ABMR rebound after daratumumab discontinuation [START_REF] Mayer | New concepts in chronic antibody-mediated kidney allograft rejection: prevention and treatment[END_REF]. Although it is difficult to decipher the role of a rescue with daratumumab added to a complex antirejection therapy, a drug that specifically deplete PC with a favorable safety profile could represent a step forward in the field.

CD38 antibodies and desensitization

The ability of CD38 to desensitize has been evaluated in both preclinical and clinical contexts and published in the same study [START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF]. The preclinical study was based on the use of daratumumab in a non-human primate model which has the most biological similarity to humans for solid organ transplant biology [START_REF] Kwun | Experimental modeling of desensitization: What have we learned about preventing AMR?[END_REF][START_REF] Kirk | Crossing the bridge: large animal models in translational transplantation research[END_REF]. The authors paired donors and recipients for maximal HLA mismatching and practiced, for allosensitization, two serial skin grafts before transplantation with a kidney from paired skin graft donor [START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF]. Daratumumab and plerixafor (anti-CXCR4), known to induce mobilization of PC from bone marrow to peripheral blood, were given as desensitization therapy with an initiation 8-12 weeks after sensitization and 8 weeks before kidney transplantation. Animals received for induction anti-CD4 and anti-CD8 antibodies and for maintenance immunosuppression tacrolimus, mycophenolate mofetil and a methylprednisolone taper. This desensitization regimen reduced significantly preformed DSA, with more than 50% reduction compared with the pretreatment time point, and prolonged graft survival with a depletion of PC without altering the germinal center response since the Tfh population was not eliminated [START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF]. However, desensitized monkeys showed delayed ABMR associated to DSA rebound and T cell-mediated rejection perhaps due to immune deviation. Indeed, the authors observed a reduction of regulatory B and T cells after desensitization with rapid emergence of activated T cells after kidney transplantation. This observation could be related to immunomodulatory effects of daratumumab but CXCR4 inhibition, due to plerixafor, is also known to limit regulatory compartment and to promote effector cells with a potential role in these cell-mediated rejection [START_REF] Poeta | Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy[END_REF]. Thus, in transplant recipients following desensitization with daratumumab, it would be interesting to elaborate new strategies than current immunosuppressive regimens in order to manage these DSA rebounds and the risk of T cell-mediated rejection. Concerning the clinical setting, the authors used daratumumab in a heart transplant candidate remaining highly sensitized after multiple courses of plasmapheresis, high-dose IVIG, and rituximab. It was observed a significant and persistent decrease of allosensitization allowing a heart transplantation six months after daratumumab infusion [START_REF] Kwun | Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use[END_REF]. Currently, based on these promising results, daratumumab are under investigation for desensitization in patients awaiting solid-organ transplantation in two clinical trial, one ruled by the nephrology department of Henri Mondor Hospital (Créteil, France) and another one directed by Stanford University (ClinicalTrials.gov, NCT04204980 and NCT04088903 (91,92)). Regarding the trial in kidney transplantation, sensitized patients with calculated panel reactive antibodies (cPRA) > 95% awaiting on the French National kidney allograft waiting-list for at least three years are eligible for the study and are randomly assigned to one of the two steps : (step 1) dose-escalation with 4 mg/kg of daratumumab weekly for four weeks, then with 8 mg/kg weekly for four weeks and then 16 mg/kg weekly for four weeks; (step 2) expansion cohort with eight weekly doses of 16 mg/kg. The primary outcomes are defined as: adverse events, intra-patient variation of cPRA and anti-HLA levels. Several other outcomes are also of interest such as percentage of patients engrafted, and intra-patient variation of ABO antibody titers (91).

Conclusion

Therapeutic improvement is required for both prevention and treatment of humoral alloresponse in solid organ transplantation. CD38 antibodies are a promising solution to profoundly deplete high affinity anti-HLA producing plasma cells. Preclinical and clinical experimental results suggests that daratumumab is a potentially therapeutic strategy to reduce DSA production and prevent and/or treat antibody-mediated rejection. However, CD38-targeting agent induce immune deviation which could be deleterious for solid organ transplants enhancing cellular-mediated rejection. Clinical studies are now needed to clarify the indications and efficacy of these promising therapeutic strategies.

546 FiguresFigure 1 .

 5461 Figures Figure 1. Immune effects of anti-CD38 antibody in the context of solid organ transplantation. ABMR: antibody mediated rejection, Breg: regulatory B cell, DSA: donor specific antibodies, PC: plasma cell, TCMR: T cell mediated rejection, Treg: regulatory T cell.

Table 1 . Selection of therapeutical regimens targeting CD38 543 544

 1

	541	Tables
	542
	Anti-CD38 strategies	Nature and mechanism	Statut	NCT number
		Daratumumab Janssen	Fully human IgG1-kappa anti-CD38 mAb	Approved	X
		Isatuximab Sanofi	Chimeric IgG1-kappa anti-CD38 mAb	Approved	X
	Felzartamab -MOR202 MorphoSys AG	Fully human IgG1-lambda anti-CD38 mAb	Ongoing in auto-immune field	NCT04733040 NCT04145440
	Mezagitamab -TAK-079 Takeda	Fully human IgG1-lambda anti-CD38 mAb	Ongoing in hemato-oncology	NCT03439280
	CID-103 CASI Pharmaceuticals	Fully human IgG1 anti-CD38 mAb	Ongoing in hemato-oncology	NCT04758767
	ISB 1342 Glennmark Phamaceuticals	CD3xCD38 bispecific antibody to redirect cytotoxic potential of T cells to CD38 + cells	Ongoing in hemato-oncology	NCT03309111
		TAK-169 Takeda	Antibody drugs conjugates: anti-CD38 Ab fragment combined to a Shiga-like toxin (payload: ribosome inactivation)	Ongoing in hemato-oncology	NCT04017130
		TAK-573
		Takeda