Alloantibody and intragraft cellular response to MHC class I-disparate kidney allografts in recipients tolerized by donor-specific transfusion and cyclosporine.
Congenic PVG.RT1u rats rapidly reject Aa class I-disparate kidney allografts from recombinant PVG R8 donors and we recently demonstrated that anti-class I MHC alloantibody plays a critical role in effecting acute rejection in this experimental model. In this article, we show that PVG.RT1u recipients can be rendered permanently and specifically tolerant to R8 kidney allografts by administration of four weekly donor-specific transfusions (DST) combined with a 7-day course of cyclosporine given with the first DST. Tolerance induction correlated with abrogation of a cytotoxic alloantibody response by thymus-independent, i.e., peripheral mechanisms; IgM and all IgG subclasses of anti-class I alloantibody were abolished. In contrast, nonrejecting kidney allografts in tolerant rats and rejecting grafts from unmodified recipients were similarly infiltrated by mononuclear cells, and intragraft transcripts for interleukin (IL)-2, interferon-gamma, and IL-13 were readily detected by reverse transcriptase polymerase chain reaction with no apparent quantitative difference between the two groups. Messenger RNA for IL-4 and IL-10 was present in rejecting grafts but barely detectable in grafts from tolerant animals. These results suggest that tolerance induction by DST and cyclosporine is, in this experimental model, associated with a selective impairment in humoral alloimmunity.
Tweedle
J R
JR
Transplant Immunology Group, Division of Immunological Science, University of Glasgow, United Kingdom.
Middleton
S E
SE
Marshall
H E
HE
Bradley
J A
JA
Bolton
E M
EM
D000818:Animals; D001483:Base Sequence; D001803:Blood Transfusion; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D006084:Graft Rejection; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000276:immunology*; D007668:Kidney / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D014019:Tissue Donors
D016207:Cytokines; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D012333:RNA, Messenger; D016572:Cyclosporine