New Insights Into the Interactions Between T-Cell Costimulatory Blockade and Conventional Immunosuppressive Drugs
- 1 November 2002
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Annals of Surgery
- Vol. 236 (5), 667-675
- https://doi.org/10.1097/00000658-200211000-00018
Abstract
To determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation. Blocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation. A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology. Cyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs. The widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.Keywords
This publication has 52 references indexed in Scilit:
- The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivoJCI Insight, 2000
- Glucocorticoids in T Cell Development and FunctionAnnual Review of Immunology, 2000
- CHRONIC BLOCKADE OF CD28-B7-MEDIATED T-CELL COSTIMULATION BY CTLA4Ig REDUCES INTIMAL THICKENING IN MHC CLASS I AND II INCOMPATIBLE MOUSE HEART ALLOGRAFTS1,2Transplantation, 1997
- Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathwaysNature, 1996
- Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis.JCI Insight, 1996
- CD40-gp39 INTERACTIONS PLAY A CRITICAL ROLE DURING ALLOGRAFT REJECTIONTransplantation, 1996
- TRANSPLANTATION TOLERANCE INDUCED BY CTLA4-Ig1Transplantation, 1994
- Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.JCI Insight, 1994
- Comparative Effects of Rapamycin Fk 506 and Cyclosporine on Antibody Production, Lymphocyte Populations and Immunoglobulin Isotype Switching in the RatImmunopharmacology and Immunotoxicology, 1993
- EXPERIMENTAL GRAFT ARTERIOSCLEROSISTransplantation, 1992