title: Treatment with a short course of LF 15-0195 and continuous cyclosporin A attenuates acute xenograft rejection in a rat-to-mouse cardiac transplantation model.
abstract: Searching for a novel immunosuppressive agent to effectively prevent acute vascular rejection (AVR) is essential for success in clinical xenotransplantation. We previously reported that Lewis rat hearts transplanted into BALB/c mice developed typical AVR in 6 days. The present study was undertaken to determine the efficacy of LF 15-0195, a new immunosuppressive analog of 15-deoxyspergualin in the prevention of AVR in a rat-to-mouse cardiac xenograft model. We transplanted 2-week old Lewis rat hearts into BALB/c mice. Four groups were included in this study: untreated recipients and cyclosporin A (CsA) treated recipients were controls; LF 15-0195 treated recipients or LF 15-0195 combined with CsA treated recipients were experimental groups. Mouse recipients received either LF 15-0195 2 mg/kg subcutaneously from day-1 to post-operative day 14, or CsA 15 mg/kg subcutaneously daily, from day 0 to endpoint rejection, or the two drugs in combination. We observed that high dose CsA did not inhibit AVR and the graft was rejected in 11.3 +/- 1.9 days. Graft histology and immunohistology showed typical AVR, characterized by interstitial hemorrhage, intravascular fibrin deposition, thrombosis, 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 AVR. When CsA 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 AVR and CMR. Sequential studies on days 6 and 14 demonstrated that LF 15-0195 either alone or combined with CsA completely inhibited antibody production. However, intragraft infiltration by Mac-1 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 AVR by markedly inhibiting the production of anti-donor IgG xAbs. Also, treatment with short course LF 15-0195 and continuous CsA significantly reduced T-cell infiltration. Studies to test this therapy in inhibiting AVR in a pig-to-non-human primate xenotransplantation model are underway.
authors.affiliation: The Multi-Organ Transplant Program, London Health Sciences Center-University Campus, 339 Windermere Road, London, Ontario N6A 5A5, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Karoline A
authors.initials: KA
authors.lastname: Hosiawa
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Shum
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutartre
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006146:Guanidines / Q000494:pharmacology*; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology
chemical_list: D000910:Antibodies, Heterophile; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D016177:Macrophage-1 Antigen; D016572:Cyclosporine