Co-stimulation blockade as a new strategy in kidney transplantation: benefits and limits.
New immunosuppressive drugs have greatly decreased the frequency of graft failure due to acute rejection but have had little impact on long-term graft survival. This is due, at least in part, to the broad non-immune effects of the current immunosuppressive drugs, which are involved in the death of patients and in chronic allograft dysfunction, particularly due to their nephrotoxicity. Recent progress in the development of biologicals, i.e. antibodies and fusion proteins, allows precise targeting of the immune system, preventing the non-immune side effects encountered with current protocols. In particular, targeting of the two most important co-stimulation pathways critical for T-cell activation, i.e. B7/CD28 and CD40/CD40L, has provided excellent results in many experimental models of organ transplantation. This has led to the clinical development of belatacept, a cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig) fusion protein, which has proved to be efficient in preventing acute rejection in kidney transplant recipients. Its use is associated with improved renal function and a better metabolic profile than calcineurin inhibitors. However, because belatacept does not selectively target alloreactive T lymphocytes and must be combined with classical immunosuppressive drugs, infectious and neoplastic complications may occur, particularly post-transplantation lymphoproliferative disorders. We also address the current development of molecules targeting other co-stimulatory pathways (CD40/CD40L, leukocyte function-associated antigen [LFA]-1/intercellular adhesion molecule [ICAM], CD2/LFA-3). Many unresolved issues regarding the use of co-stimulation blocking agents are also discussed, e.g. their long half-life, which can be problematic in cases of serious adverse events, their long-term safety and efficacy, and the lack of monitoring tools to allow modulation of their use over time.
Snanoudj
Renaud
R
Service de Transplantation Rénale Adulte, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France. renaud.snanoudj@nck.aphp.fr
Zuber
Julien
J
Legendre
Christophe
C
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects* / Q000379:methods*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D058990:Molecular Targeted Therapy; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D007166:Immunosuppressive Agents; D023201:CD40 Ligand