Farnesyltransferase inhibitors (FTIs), developed as anti-cancer drugs, have the potential to modulate immune responses without causing nonspecific immune suppression. We have investigated the possibility that FTIs, by affecting T cell cytokine secretion, can attenuate alloreactive immune responses. The effects of FTIs on murine alloreactive T cells were determined both in vitro, by measuring cytokine secretion or cell proliferation in mixed lymphocyte cultures, and in vivo, by performing skin allografts from H-2(bm12) mice to MHC class II-disparate B6 mice. We found that two different FTIs, ABT-100 and L-744,832, blocked secretion of IFN-gamma, IL-2, IL-4, and TNF-alpha from naïve T cells in vitro. ABT-100 and L-744,832 blocked cytokine production from both CD4(+) and CD8(+) naïve T cells stimulated with CD3 and CD28 antibodies, but only if the cells were pretreated with the FTIs for 48 h. Proliferation of alloreactive T cells in mixed lymphocyte cultures was blocked by either FTI. We also found that the proliferation of enriched T cells stimulated with IL-2 was blocked by ABT-100 treatment. In mice with an MHC class II-disparate skin graft, rejection of primary allografts was significantly delayed by treatment with either ABT-100 or L-744,832. Secondary rejection in mice previously primed to the alloantigen was found to be unaffected by L-744,832 treatment. We have shown that FTIs can block T cell cytokine secretion and attenuate alloreactive immune responses. The ability of FTIs to block secretion of cytokines, including IFN-gamma and IL-4, from naïve T cells provides a likely biological mechanism for the specific suppression of class II MHC-mediated allorejection. These results demonstrate that FTIs may have useful immunomodulatory activity due to their ability to delay priming to alloantigens.
We are investigating the possibility that farnesyl transferase inhibitors (FTIs) may be useful anti‐rejection drugs. We have shown that the FTI, L‐744,832 can significantly delay allograft rejection in mice using MHC class II mismatched skin allografts. When treatment with this FTI begins two days prior to the allograft procedure and extends for 5 days, we found that rejection was delayed in all treated mice, 26±14 days, compared to untreated mice, 13±4 days. Interestingly, this delay in rejection can extend for greater than 30 days in 30% of the treated mice. To determine whether FTI treatment can delay alloreactive effector responses, we examined the effect of L‐744,832 treatment on allograft rejection in mice that had previously been sensitized to the allo‐antigens. We found that treatment with this FTI did not significantly delay second‐set allograft rejection. This observation, coupled with the long delay in some of the first set allograft treatments, suggests that FTIs may be able to induce tolerance of the alloreactive CD4+ T cells. To further investigate the action of FTIs on graft rejection we are measuring the effects of treatment using mixed lymphocyte cultures and using in vivo tolerance assays. We suggest that FTIs may modulate acute immune responses without systemically suppressing the immune system.
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