One-year monkey heart xenograft survival in cyclosporine-treated baboons. Suppression of the xenoantibody response with total-lymphoid irradiation.
The shortage of cadaveric human organs for transplantation could be alleviated by the use of xenografts. Long-term (> one-year) survival of xenografts in humans or experimental animals has not been achieved with previous immunosuppressive protocols. Poor results in xenotransplantation compared with allotransplantation have been attributed to a more potent antibody response rather than to cell-mediated responses. To investigate these issues a concordant heterotopic cardiac xenograft model was developed in conjunction with cyclosporine and/or total-lymphoid irradiation. Concordant models permit examination of xenoantigen induced antibody and cell-mediated responses since preformed humoral factors (in discordant models) do not cause hyperacute rejection. Four groups of baboon recipients received cervical heart transplants from cynomolgous monkeys. Group I (n = 2), untreated, mean survival (MS) = 6 days; group II (n = 5), CsA and methylprednisolone, MS = 25 days; group III (n = 3), preoperative TLI, MS = 29 days; group IV (n = 6), preoperative TLI and CsA+MP, MS = 255 days (> 77, > 108, > 142, 184, > 480, 540 days). Heart xenografts of CsA-MP-treated recipients appear to be destroyed predominantly by antibody (IgM)-mediated processes whereas cell-mediated rejection is likely the major reaction in TLI-treated recipients. CsA-MP-treated recipients had early immunohistochemical evidence of antibody and complement-mediated rejection (deposition of IgM and complement but not IgG on heart xenografts). In contrast IgM and complement deposits were not detected on heart xenografts in TLI- and TLI-CsA-treated recipients. IgG xenoantibodies were only detected on the two rejected heart grafts of TLI-CsA-treated recipients. CsA-MP-treated recipients rapidly developed high xenoantibody titers (1:256 to 1:512) that immediately preceded rejection. In contrast, TLI-treated animals developed lower levels of xenoantibody (< or = 1:8) and TLI-CsA-treated recipients had no detectable xenoantibody during the initial three months after transplantation (and titers no greater than 1:8 thereafter.) The lack of xenoantibody was likely not due to a generalized inhibitory effect of the immunosuppressants on B cell function since all classes of serum immunoglobulins were in the normal range. Intragraft cytolytic lymphocyte activity was detected in rejecting TLI- and TLI-CsA-treated recipients but could not be detected in xenografts of CsA-MP-treated recipients. One explanation for these data is that TLI (either directly or indirectly) induces a state of specific B cell unresponsiveness to monkey xenoantigens, thereby preventing IgM mediated rejection in the third week after transplantation.(ABSTRACT TRUNCATED AT 400 WORDS)
Roslin
M S
MS
Department of Surgery, Maimonides Medical Center, Brooklyn 11219.
Tranbaugh
R E
RE
Panza
A
A
Coons
M S
MS
Kim
Y D
YD
Chang
T
T
Cunningham
J N
JN
Norin
A J
AJ
D000818:Animals; D000917:Antibody Formation / Q000528:radiation effects*; D016572:Cyclosporine / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects* / Q000528:radiation effects; D007150:Immunohistochemistry; D007959:Lymphocyte Culture Test, Mixed; D008221:Lymphoid Tissue / Q000528:radiation effects*; D008252:Macaca fascicularis; D009206:Myocardium / Q000737:chemistry; D010215:Papio; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*; D014916:Whole-Body Irradiation
D016572:Cyclosporine