Immunosuppression | EPFL Graph Search

L'immunosuppression est l'inhibition de l'activation du système immunitaire. Elle peut être induite par une intoxication (le plomb responsable du saturnisme par exemple a une composante immunotoxique), la radioactivité, certaines maladies (VIH/sida...) ou naturellement enclenchée par l'organisme dans certaines conditions. Elle est parfois volontairement induite pour des raisons médicales (pour éviter un rejet de greffe par exemple). Typologies Cette immunosuppression peut être

naturelle. Elle se produit pour éviter l'« emballement » du système immunitaire. Ainsi, à la suite d'une hyper-inflammation induite par le système immunitaire, à la suite d'une infection ou d'un traumatisme sévère, ou encore d'une allergie, la réponse immunitaire va alors normalement se réguler pour entrer dans une phase d'immunosuppression, ceci permettant de retrouver progressivement un état d'homéostasie de l'organisme.
médicalement provoquée. Des immunosuppresseurs sont alors utilisés.

Islet Encapsulation: New Developments for the Treatment of Type 1 Diabetes

Léo Bühler, Sandrine Gerber, Yi Wang, Qixing Zhang

Islet transplantation is a promising approach for the treatment of type 1 diabetes (T1D). Currently, clinical islet transplantation is limited by allo - and autoimmunity that may cause partial or complete loss of islet function within a short period of time, and long-term immunosuppression is required to prevent rejection. Encapsulation into semipermeable biomaterials provides a strategy that allows nutrients, oxygen and secreted hormones to diffuse through the membrane while blocking immune cells and the like out of the capsule, allowing long-term graft survival and avoiding long-term use of immunosuppression. In recent years, a variety of engineering strategies have been developed to improve the composition and properties of encapsulation materials and to explore the clinical practicality of islet cell transplantation from different sources. In particular, the encapsulation of porcine islet and the co-encapsulation of islet cells with other by-standing cells or active ingredients for promoting long-term functionality, attracted significant research efforts. Hydrogels have been widely used for cell encapsulation as well as other therapeutic applications including tissue engineering, cell carriers or drug delivery. Here, we review the current status of various hydrogel biomaterials, natural and synthetic, with particular focus on islet transplantation applications. Natural hydrophilic polymers include polysaccharides (starch, cellulose, alginic acid, hyaluronic acid, chitosan) and peptides (collagen, poly-L-lysine, poly-L-glutamic acid). Synthetic hydrophilic polymers include alcohol, acrylic acid and their derivatives [poly (acrylic acid), poly (methacrylic acid), poly(acrylamide)]. By understanding the advantages and disadvantages of materials from different sources and types, appropriate materials and encapsuling methods can be designed and selected as needed to improve the efficacy and duration of islet. Islet capsule transplantation is emerging as a promising future treatment for T1D.

2022

Guidance molecule SEMA3A restricts tumor growth by differentially regulating the proliferation of tumor-associated macrophages

Margarita Bartish, Michele De Palma, Mario Leonardo Squadrito, Tatjana Wallmann

Accumulation of tumor-associated macrophages (TAM) correlates with malignant progression, immune suppression and poor prognosis. In this study, we defined a critical role for the cell-surface guidance molecule SEMA3A in differential proliferative control of TAMs. Tumor cell-derived SEMA3A restricted the proliferation of pro-tumoral M2 macrophages but increased the proliferation of anti-tumoral M1, acting through the SEMA3A receptor neuropilin-1 (NP1). Expansion of M1 macrophages in vivo enhanced the recruitment and activation of NK cells and cytotoxic CD8+ T cells to tumors, inhibiting their growth. In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8+ T cells and NK cells, while inversely correlating with established characters of malignancy. In summary, our results illuminate a mechanism whereby the TAM phenotype is controlled, and identify the cell surface molecule SEMA3A as a candidate for therapeutic targeting.

American Association for Cancer Research2016

Synthèse, structure et propriétés physicochimiques des cyclosporines

Olivier Turpin

Cyclosporin is a cyclic undecapeptide useful as drug for organ transplantation due to its immunosuppressive properties. Ten years ago, an anti-viral activity was discovered, incompatible with immunosuppression. These two activities originate in the presence of two receptors, i.e. cyclophiline A, which interferes in two processes and calcineurine, regulating immunosuppression. Consequently, the synthesis of modified analogues at different positions represents a research domain of high importance for elucidating structure-activity relationships of these receptors. Position 2 of cyclosporin is in close contact to cyclophiline and, consequently, of particular interest. cyclosporin C (CsC) differs from the well-known immunosuppressive analogue cyclosporin A (CsA) by the presence of a trifunctional amino acid at position 2, i.e. a threonine residue replacing 2-amino butyric acid (Abu2) in CsA. While the biological and pharmacokinetic properties of CsC and CsA are very similar, the presence of the threonine makes CsC a most attractive candidate for structure-activity relationship studies in applying the pseudo-proline concept (ΨPro) developed in the group of Prof. M. Mutter. The advantage of this concept relies in the direct incorporation of the pseudoproline moiety into CsC by cyclocondensation of ketals with yields reaching up to 60%, depending on the substituents R1 et R2 (figure 1). Figure 1: Direct insertion of the pseudo-proline system into CsC NMR analysis showed that monosubstitutions at C2 strongly effect the conformational properties. For example, unique conformations were found in weakly polar (CDCl3) and polar solvents (DMSO), depending on R1/R2. In contrast, the simultaneous presence of R1 and R2 result in intermediate effects. The drastic conformational impact on the Cs backbone by the invertion of ΨPro-systems is manifested by the loss of biological activity. Based on these results, the ΨPro concept was applied for the synthesis of so-called soft prodrugs of CsC. As prototype, a derivative containing a phosphate group (R1 = 3,5-Dimethoxy-4-phosphonooxyphenyle; R2 = H) improved the water solubility of cyclosporin by a factor higher than 500. The developed strategies can be applied to any peptide featuring a threonine or serine in its primary sequence, paving the way to a new class of prodrugs. With the goal to obtain analogues of higher receptor selectivity, the second part of the thesis focuses on the modification of position 8 of cyclosporin. Most notably, located in the effector domain of calcineurin, modifications of residue D-Ala8 should prevent the binding of the dimeric complex Cs-cyclophiline A to calcineurin, a prerequisite for antiviral and non-immunosuppressive activity. Based on experiments on the alkylation of CsA at D-NAla8, a selective ring-opening procedure of CsA between residues Ala7 and D-Ala8 was elaborated in three major steps: Selective alkylation of the nitrogen of D-Ala8 in 43% yield (5 steps), N —> O acyl transfer of Ala7 (>70%) and a solvolysis followed by Edman degradation to the linear decapeptide in 24.5% yield. Starting from CsA, the linear decapeptide was obtained on 10.5% overall yield for 10 steps (figure 2). Figure 2: Retrosynthesis of the 7-8 ring-opening of CsA While the reported ring opening procedures allow the study of the influence of modifications on positions 11 to 5 of Cs, the elaborated strategy gives access to the efficient modification of key position 8, opening interesting perspectives for structureactivity relationship studies of high therapeutical potential.