Attenuation of acute xenograft rejection by short-term treatment with LF15-0195 and monoclonal antibody against CD45RB in a rat-to-mouse cardiac transplantation model.

BACKGROUND

We previously reported that Lewis rat hearts transplanted into BALB/c mice developed typical acute vascular rejection (AVR). The present study was undertaken to determine the efficacy of LF15-0195, a new analogue of 15-deoxyspergualin, in the prevention of AVR and to determine whether a combination of LF15-0195 and CD45RB monoclonal antibody (mAb) would have a synergistic effect in prolonging xenograft survival.

METHODS

We transplanted 2-week-old Lewis rat hearts into BALB/c mice, followed by experimental immunosuppressive regimens. Control groups were either untreated or treated with mAb monotherapy (100 microg/mouse, days -1 to 7, intravenously). Experimental groups were either treated with LF15-0195 (2 mg/kg, days -1 to 14, subcutaneously) or with LF15-0195 combined with mAb at monotherapeutic doses.

RESULTS

Heart xenografts in both untreated and mAb-treated BALB/c recipients were rejected at 6.0+/-0.7 days and 8.5+/-1.3 days, respectively, with typical features of AVR, characterized by hemorrhage, fibrin deposition, thrombosis, and massive accumulations of anti-rat IgG and IgM. Serum xenoreactive antibodies (xAbs) were also markedly elevated in these animals. In contrast, LF15-0195 monotherapy significantly prolonged graft survival to 19.3+/-0.7 days. Notably, xAbs were significantly decreased and graft rejection was of a cell-mediated nature instead of AVR. When mAb was combined with LF15-0195, graft survival was further increased to 65.2+/-9.1 days. Antibody production and T-cell infiltration were significantly inhibited at terminal stages of graft survival. Sequential studies on days 6 and 14 demonstrated that LF15-0195, either alone or combined with mAb, completely inhibited antibody production. However, intragraft infiltration by Mac-1+ cells in LF15-0195-treated recipients was similar to that of untreated recipients.

CONCLUSIONS

LF15-0195 effectively attenuated AVR by markedly inhibiting antidonor xAb production. Treatment with a combination of LF15-0195 and CD45RB mAb also significantly reduced T-cell infiltration and should be studied further to evaluate its efficacy in nonhuman primate subjects.