Viral IL-10-induced immunosuppression requires Th2 cytokines and impairs APC function within the allograft.
Previous reports demonstrated that retroviral mediated gene transfer of viral IL-10 (vIL-10) prolongs allograft survival by decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and IL-2-secreting helper T lymphocyte precursor (HTLp) frequency within graft-infiltrating cells (GIC). This report now shows that vIL-10 efficacy is dependent on CD4(+) T cells, suggesting that immunosuppression may involve a switch from a Th1 to a Th2 alloresponse. In support of this, anti-IL-4 or anti-murine IL-10 (anti-mIL-10) mAbs, but not anti-IFN-gamma mAb, administered at the time of vIL-10 gene transfer prevents enhanced graft survival. Because Th switching involves APC function, GIC were examined for their ability to present alloantigen. GIC from vIL-10-treated grafts were shown to be mostly of recipient (CBA) origin, yet were unable to elicit alloproliferative responses from donor type (C57BL/6) or third party (BALB/c) responders. The inability of vIL-10-treated GIC to stimulate the MLR was not due to the generation of negative regulatory cells or the production of immunosuppressive cytokines such as IL-4, mIL-10, or TGFbeta. Using fractionated GIC subpopulations, the number of recipient type cells in the allografts was modestly reduced by vIL-10 gene transfer, while maintaining both APC phenotype and alloantigen presenting function. Conversely, after vIL-10 gene transfer, donor type GIC were unable to participate in direct alloantigen presentation. Therefore, local immunosuppression induced by vIL-10 gene transfer is CD4 T cell and IL-4 and mIL-10 dependent, and impairs direct alloantigen presentation through an alteration of donor type APC function.
Qin
L
L
Department of Pathology, Institute for Gene Therapy and Molecular Medicine, and the Recacati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Ding
Y
Y
Tahara
H
H
Bromberg
J S
JS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D005260:Female; D018014:Gene Transfer Techniques; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance / Q000235:genetics; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D007519:Isoantigens / Q000276:immunology / Q000378:metabolism; D007958:Leukocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics
D000911:Antibodies, Monoclonal; C066460:BCRF1 protein, Human herpesvirus 4; D015704:CD4 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D007519:Isoantigens; D014764:Viral Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma