Topical inhibition of T cell costimulatory pathways in draining lymph nodes may suppress allograft rejection

Abstract

Topical immune suppression is an attractive and practical therapeutic option to prolong survival time of allografts, before the appearance of new agent with higher immunosuppressive efficacy and lower undesirable side effects. The initiation of rejection and outcome of allografts is principally mediated by alloantigen reactive T cells. The activation of T cells requires at least two signals, first is T-cell receptor signal and second is costimulatory signal. T cells that encounter antigen without the appropriate costimulatory signal become anergy or tolerance. Migration of alloantigen-bearing dendritic cells into the T-cell zone of secondary lymphoid tissues, which are essential for primary alloimmune responses, effectively induces T-cell activation and expansion with the presence of two signals. Draining lymph nodes are the promising targets for topical immune suppression, as disrupting lymphatic drainage from the transplanted graft to lymph nodes prevented rejection of skin allografts and lymphadenectomy prolong the survival time of skin and corneal allografts in experimental animals. Therefore, we hypothesize that inhibition of T cell costimulatory pathways in draining lymph nodes could impair the alloantigen-specific immune response and reduce systemic immunosuppressive drugs dose for allografts survival. Further investigations are required to identify most efficient way for draining lymph nodes transfer of costimulatory molecule gene or topical drug administration of costimulatory inhibitors to draining lymph nodes.