Use of allochimeric proteins to mitigate graft-versus-host and host-versus-graft immune responses to rat small bowel allografts.
BACKGROUND
We aimed to identify the polymorphic epitopes that mitigate graft-versus-host disease (GvHD) and host-versus-graft response (HvGR) toward rat small bowel allografts in rats.


METHODS
We tailored class I major histocompatibility complex (MHC) allochimeric antigens encoding 10 al-helical (alpha(1h)l58-80-RT1.Aa) or 4 (alpha(1h)l/u62-69-RT1.Aa) polymorphic amino acids. In the GvHD model, ACI (RT1a) donors were pretreated (day -14) with an intrathymic injection of alpha(1h)l58-80-RT1.Aa, alpha(1h)l/u62-69-RT1.Aa, or RT1.Al protein, with or without simultaneous intravenous injection of anti-T-cell receptor R73 monoclonal antibodies. Wistar-Furth (WF; RT1u) donors were tested with a similar protocol. In the HvGR model, ACI recipients were treated with a protocol designed to induce transplantation tolerance toward WF heart allografts: a portal vein injection of alpha(1h)l/u62-69-RT1.Aa protein and cyclosporine (4 mg/kg, intramuscular; days 0-6).


RESULTS
GvHD was prevented in all (ACI x LEW) F1 recipients (RT1a/l) by pretreating ACI donors with R73 monoclonal antibody and recipient RT1.Al or alpha(1h)l58-80-RT1.Aa protein. Similarly, pretreatment of WF donors with RT1.Aa protein also prevented GvHD in (ACI x WF) F1 recipients. However, in a combined GvHD/HvGR model, ACI recipient perioperative treatment designed to prevent HvGR only modestly prolonged WF small bowel allograft survival (27.7+/-5.3 days compared to 17.4+/-4.6 days in the cyclosporine-alone group). In contrast, application of the two protocols significantly prolonged WF allograft survival (55.6+/-34.6 days), with two of seven recipients surviving more than 100 days.


CONCLUSIONS
Simultaneous inhibition of GvHD and HvGR significantly prolongs small bowel allograft survival.
Okamoto
M
M
Department of Surgery, University of Texas Medical School, Houston 77030, USA.
Stepkowski
S M
SM
Wang
M
M
Kahan
B D
BD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D015395:Histocompatibility Antigens Class I / Q000627:therapeutic use; D006789:Host vs Graft Reaction / Q000187:drug effects / Q000276:immunology; D016056:Immunodominant Epitopes / Q000627:therapeutic use; D007421:Intestine, Small / Q000637:transplantation*; D007519:Isoantigens / Q000494:pharmacology; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D007519:Isoantigens; D011993:Recombinant Fusion Proteins