Negative T-cell costimulatory pathways: their role in regulating alloimmune responses.
OBJECTIVE
Negative T-cell costimulatory pathways regulate T-cell responses and are of great interest in the development of tolerance-inducing strategies in transplantation. This article provides an update of major contributions to the understanding of the known negative costimulatory pathways, and reviews recent studies on the effects of targeting of these pathways in alloimmunity.


RESULTS
Graft tissue expression of negative costimulatory molecules, especially programmed death receptor ligand 1, plays a major role in regulation of alloimmune responses. The recently demonstrated programmed death receptor ligand 1:B7-1 interaction highlights the complexity and possible redundancy/hierarchy of the functions of these pathways in vivo. CD160 was identified as a ligand of Herpes virus entry mediator and has been established as a new coinhibitory molecule. A soluble form of B7-H3 with possible functional roles has been identified in mice and humans.


CONCLUSIONS
The understanding of negative costimulatory pathways is embarrassed by complex interactions between simultaneously activated positive and negative costimulatory pathways among themselves and with immunosuppressive agents, differential expression of these molecules on different immune cell subsets as well as their expression in parenchymal cells of transplanted tissues, all of them clearly affecting their functions. Further elucidation of these novel concepts is pertinent for targeting these pathways in translational studies in near future.
Boenisch
Olaf
O
Transplantation Research Center, Brigham and Woman's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Sayegh
Mohamed H
MH
Najafian
Nader
N
D000818:Animals; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D016377:Organ Transplantation / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects
D007166:Immunosuppressive Agents