B7‐H3 promotes acute and chronic allograft rejection

Abstract

The B7 homolog B7-H3 is important for the regulation of immune responses though its functions in vivo are controversial. We report the first clinical and experimental data concerning expression and function of B7-H3 in alloresponses. Immunohistological and molecular analyses showed B7-H3 expression by cells mediating rejection of human and mouse allografts. To analyze the significance of B7-H3 in rejecting allografts, we generated B7-H3 -/-mice and showed that targeting of B7-H3 was synergistic with other forms of immune modulation; e.g. a regimen of rapamycin gave 12-14 days of survival in wild-type controls but led to permanent cardiac and islet allograft survival in B7-H3 -/-mice. Cardiac allografts in treated B7-H3 -/-mice showed markedly decreased production of key cytokine, chemokine and chemokine receptor mRNA transcripts as compared to wild-type controls. The incidence of chronic rejection in two different cardiac allograft models was also inhibited in B7-H3 -/-as compared to wild-type recipients. Lastly, in addition to the expected antigen-presenting cell expression of B7-H3, CD4 and CD8 T cells showed B7-H3 induction upon cell activation, and both dendritic cell-and T cell-expressed B7-H3 each enhanced T cell proliferation in vitro and in vivo. We conclude that B7-H3 promotes T cell-mediated immune responses and the development of acute and chronic allograft rejection.

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

“…In contrast to reports in humans, tumor expression of B7-H3 enhances cytotoxicity (21,22). And when B7-H3 knockout mice are used in allograft survival studies, B7-H3-deficient transplants fare better when combined with immunosuppression (23). Thus far, there appears to be no specific and consistent association of the two Ig-like or four Ig-like B7-H3 domain with activating or inhibitory effects.…”

“…Similar to the other B7 family members, subsequent studies have shown that B7-H3 can mediate inhibitory effects (17,19,20) on T cell function as well as costimulatory effects (15,(21)(22)(23). Unlike B7-1 and B7-2, B7-H3 has been shown to also be expressed on nonhemopoietic cells (17).…”

Clinical importance of B7-H3 expression in human pancreatic cancer

“…It was originally identified as a co-stimulatory molecule that promotes T-cell proliferation and IFN-g production (Chapoval et al, 2001). The experimental evidence that acute and chronic cardiac allograft rejection can be reduced in B7-H3 knockout mice further supports a stimulatory role for B7-H3 on T cells (Wang et al, 2005). By contrast, B7-H3 has been shown to impair type 1 T-helper cell responses and inhibit cytokine production (Suh et al, 2003).…”

“…B7-H3 is thought to serve as an accessory co-regulator of T-cell responses after initial antigen priming. At present, there is no consensus with regard to the physiological and pathological roles of B7-H3, as both immunological stimulatory and inhibitory functions have been described (Chapoval et al, 2001;Sun et al, 2002;Suh et al, 2003;Castriconi et al, 2004;Prasad et al, 2004;Steinberger et al, 2004;Wang et al, 2005;Zhang et al, 2005). It was originally identified as a co-stimulatory molecule that promotes T-cell proliferation and IFN-g production (Chapoval et al, 2001).…”

The contrasting role of B7-H3

“…In these mouse cancer models, it seems that tumor-associated B7-H3 preferentially regulates CD4-independent induction of CD8 CTL responses. B7-H3 action through T cell costimulation is also implied by the fact that rapamycin treatment induced permanent cardiac and islet allograft survival in B7-H3 knockout mice (17), indicating that B7-H3 functions to promote T cell responses that mediate acute and chronic allograft rejection. These lines of evidence have now been augmented by the work showing that B7-H3 functions through the TLT-2 receptor on CD8 T cells as a costimulator (4).…”