MD-1 expression regulates direct and indirect allorecognition.
Expression of the molecule MD-1 was previously described to regulate allogeneic and xenogeneic skin graft survival, as documented by the decrease in rejection seen following functional blockade of MD-1 expression in vivo, using antisense oligodeoxynucleotides (ODNs) or anti-MD-1 antibodies. It was unclear from these data whether blockade of expression of MD-1 on donor or recipient cells was crucial. We have investigated the effect on allorecognition of treating skin graft donors, and/or recipients, of either fully major histocompatibility complex (MHC)-mismatched allogeneic skin grafts (C3H with C57BL/6 grafts and vice versa) or grafts differing at only multiple minor alloantigens (C3H with B10.BR grafts; C57BL/6 with C3H.SW), with antisense ODNs to MD-1, or in some cases, following transplantation of class II-deficient cells into class I-deficient mice. Graft-specific cytotoxic T lymphocytes (CTLs) were measured in spleen cells recovered at sacrifice of recipients and following donor-specific restimulation in vitro. In the latter case, we also measured cell proliferation and (by enzyme-linked immunosorbent assay) production of interleukin-2 (IL-2)/interferon-gamma (IFN-gamma) or IL-4/IL-10 in vitro (nominal type-1 vs type-2 cytokines). CTL responses to minor-incompatible grafts were diminished, only if graft recipients were treated with ODNs. However, treatment of graft donor and/or recipient of MHC-incompatible grafts produced inhibition of CTL production. Optimal inhibition came from treating both. Specific suppression of CTL production coincided with inhibition of proliferation and preferential production of IL-4 and IL-10 at the expense of IL-2 and IFN-gamma. Our data are consistent with the hypothesis that MD-1 expression regulates both the direct and indirect pathways of allorecognition and that regulation of MD-1 expression may thus help regulate clinical graft rejection.
Hadidi
S
S
Transplant Research Division, The Toronto Hospital, Toronto, Ontario, Canada. sima.hadidi@tbrc.mgh.harvard.edu
Gorczynski
R M
RM
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D002455:Cell Division; D004797:Enzyme-Linked Immunosorbent Assay; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control* / Q000628:therapy; D006085:Graft Survival / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007519:Isoantigens; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D000954:Antigens, Surface; D007376:Interleukin-2; D007519:Isoantigens; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma