Treatment with a short course of LF 15-0195 and continuous @entity205 attenuates acute xenograft rejection in a XXXX -to- @entity19 cardiac transplantation model.

@entity1 @entity1707 @entity548 @entity870 @entity19 @entity1294 @entity5101 @entity205 @entity35 @entity715 @entity3804
Searching for a novel immunosuppressive agent to effectively prevent @entity1294 ( @entity1294 ) is essential for success in clinical xenotransplantation. We previously reported that Lewis @entity35 hearts transplanted into BALB/c @entity19 developed typical @entity1294 in 6 days. The present study was undertaken to determine the efficacy of LF 15-0195, a new immunosuppressive analog of @entity5101 in the prevention of @entity1294 in a @entity35 -to- @entity19 cardiac xenograft model. We transplanted 2-week old Lewis @entity35 hearts into BALB/c @entity19 . Four groups were included in this study: untreated recipients and @entity205 ( @entity870 ) treated recipients were controls; LF 15-0195 treated recipients or LF 15-0195 combined with @entity870 treated recipients were experimental groups. @entity19 recipients received either LF 15-0195 2 mg/kg subcutaneously from day-1 to post-operative day 14, or @entity870 15 mg/kg subcutaneously daily, from day 0 to endpoint rejection, or the two drugs in combination. We observed that high dose @entity870 did not inhibit @entity1294 and the graft was rejected in 11.3 +/- 1.9 days. Graft histology and immunohistology showed typical @entity1294 , characterized by interstitial @entity548 , intravascular fibrin deposition, @entity715 , and massive deposition of anti-rat immunoglobulin G (IgG) and immunoglobulin M (IgM). Serum xenoreactive antibodies (xAbs) were markedly elevated in these animals as well. In contrast, we observed that treatment with LF 15-0195 alone significantly prolonged graft survival to 19.3 +/- 0.7 days. Notably, xAbs were significantly decreased and the rejection pattern of these grafts was cell-mediated rejection (CMR), instead of @entity1294 . When @entity870 was combined with LF 15-0195, the graft mean survival time was further increased to 58.5 +/- 17.3 days. Antibody production and T-cell infiltration were significantly inhibited at the terminal stages of graft survival and pathology showed striking attenuation of both @entity1294 and CMR. Sequential studies on days 6 and 14 demonstrated that LF 15-0195 either alone or combined with @entity870 completely inhibited antibody production. However, intragraft infiltration by @entity3804 positive cells including natural killer cells, macrophages and granulocytes in LF 15-0195 treated recipients was similar to that of untreated recipients. We conclude that LF 15-0195 effectively prevented @entity1294 by markedly inhibiting the production of anti-donor IgG xAbs. Also, treatment with short course LF 15-0195 and continuous @entity870 significantly reduced T-cell infiltration. Studies to test this therapy in inhibiting @entity1294 in a @entity1707 -to-non- @entity1 primate xenotransplantation model are underway.
