The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

Abstract

The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-γ-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 ± 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 ± 2.8 days) as did CTLA4Ig (MST: 21.5 ± 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 ± 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.

In Vivo Helper Functions of Alloreactive Memory CD4+ T Cells Remain Intact Despite Donor-Specific Transfusion and Anti-CD40 Ligand Therapy

“…Novel strategies, including the use of reagents that are known to synergize with costimulatory blockade in prolonging allograft survival (for example, rapamycin and 15-deoxyspergualin) (24,41,55,56), are attractive, but their specific effect on memory T cells needs to be evaluated in detail. Finally, recent studies have provided evidence that certain newly recognized costimulatory pathways, such as ICOS/B7RP-1 and OX40/OX40L (CD134/CD134L), may be involved in reactivation of memory T cells, but have little effect on naive T cells (57)(58)(59)(60)(61). Targeting these novel pathways (in combination with CD40/CD40L blockade) is a promising, although still unproven approach for inhibiting alloreactive memory CD4 ϩ T cell function in vivo.…”

Memory T Cells and Their Costimulators in Human Allograft Injury

“…ICOS deficiency or blockade have also been shown in rodent models to improve transplant survival and, in conjunction with B7 blockade, even induce tolerance (56,57), although not in all cases (58). OX40L blockade also leads to increased graft survival in presensitized mice in combination with B7 blockade (58,59). When any of these pathways are blocked in our chimeric model of human memory, we show significantly decreased endothelial damage, vascular destruction, and effector molecule mRNA at 10 days, although none seems to be as effective as blockade of LFA-3.…”

Costimulation and Autoimmune Diabetes in BB Rats

“…CD28-CD80/86 costimulation was blocked using CTLA4-Ig (30), anti-CD80 mAb and/or anti-CD86 mAb (31). CD134-CD134L costimulation was blocked using anti-CD134L mAb (29,39). The control isotype mAb was injected using the same dose and schedule.…”