Suppression of delayed xenograft rejection by specific depletion of elicited antibodies of the IgM isotype.
BACKGROUND
Hamster hearts transplanted into untreated rats undergo delayed xenograft rejection (DXR). This acute inflammatory response is associated with the deposition of anti-graft antibodies of the immunoglobulin (Ig)M isotype in the vasculature. We have previously shown that these antibodies are generated in a T cell-independent manner. In this study, we tested whether the generation of anti-graft IgM antibodies is involved in the pathogenesis of DXR. In addition, we tested whether the suppression of this antibody response would overcome DXR.


METHODS
Hamster hearts were transplanted into rats treated with an anti-mu monoclonal antibodies (mAb) to deplete circulating IgM or with an isotype-matched control mAb recognizing the dinitrophenyl epitope. T cell immunosuppression was achieved with cyclosporin A (CsA).


RESULTS
Depletion of circulating IgM by anti-mu mAb inhibited DXR, whereas the control mAb had no effect on DXR. In anti-mu-treated rats, xenografts were rejected 5-7 days after transplantation through a T cell-dependent mechanism associated with the generation of antibodies of the IgG isotype. Combination of anti-mu with CsA suppressed the anti-graft IgM and IgG response and resulted in long-term xenograft survival (> 50 days). Xenograft long term survival occurred despite the return of anti-graft IgM antibodies to the circulation, a phenomenon referred to as accommodation.


CONCLUSIONS
This study demonstrates that the pathogenesis of DXR can be initiated by anti-graft antibodies of the IgM isotype, which are generated in a T-cell independent manner. In addition, we show that under T cell immunosuppression, specific depletion of this IgM response by anti-mu mAb administration results in xenograft long-term survival and accommodation.
Sato
K
K
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Takigami
K
K
Miyatake
T
T
Czismadia
E
E
Latinne
D
D
Bazin
H
H
Bach
F H
FH
Soares
M P
MP
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000166:cytology; D006224:Cricetinae; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000097:blood / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D008297:Male; D008647:Mesocricetus; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology; D014183:Transplantation, Heterologous / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C044203:anti-IgM; D016572:Cyclosporine