Regulation of transplant arteriosclerosis by CD25+CD4+ T cells generated to alloantigen in vivo.
BACKGROUND
CD25+CD4+ regulatory T cells have been shown to suppress alloimmunity in various experimental settings. Here, we hypothesized that alloantigen-reactive regulatory T cells would reduce the severity of transplant arteriosclerosis.


METHODS
CD25+CD4+ T cells from CBA mice that were pretreated with C57BL/6 (B.6) blood (donor-specific transfusion, DST) and nondepleting anti-CD4 Ab (YTS 177) were cotransferred with naïve CBA CD25-CD4+"effector" T cells into CBA-rag-/- mice. These animals received aorta transplants from B.6 CD31-/- donors. CBA wild-type recipients of B.6 aorta grafts were pretreated with 177/DST directly. Some animals received 6x10(5) CD25+CD4+ T cells from pretreated mice to augment regulation on day -1. Grafts were harvested on day 30.


RESULTS
Luminal occlusion of the graft caused by neointima formation was 29.3+/-19.4% (n=5) after transfer of effector T cells only. Co-transfer of CD25+CD4+ regulators reduced occlusion significantly (2.4+/-3.3%, n=3; P=0.009). This effect was partially abrogated in the presence of a CTLA4 blocking Ab (11.1+/-4.7%, n=4; P=0.008). Pretreating immunocompetent CBA recipients of B.6 aortic allografts with 177/DST did not reduce transplant arteriosclerosis significantly (43.0+/-15.7%, n=5 vs. 56.6+/-16.8%, n=5; 177/DST vs. controls; P=0.22). However, when pretreated primary CBA recipients received an additional transfer of 6 x 10(5) CD25+CD4+ T cells procured from other mice pretreated with 177/DST before transplantation, luminal occlusion of the graft was markedly reduced (33.0+/-7.6%, n=5; P=0.002).


CONCLUSIONS
Regulatory T cells generated in vivo to alloantigen can prevent CD25-CD4+ T-cell-mediated transplant arteriosclerosis. In immunocompetent recipients, these cells have potential to be used as cellular immunotherapy to control transplant arteriosclerosis.
Warnecke
Gregor
G
Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Bushell
Andrew
A
Nadig
Satish N
SN
Wood
Kathryn J
KJ
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D001011:Aorta / Q000637:transplantation*; D001161:Arteriosclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001803:Blood Transfusion; D015704:CD4 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D004730:Endothelium, Vascular / Q000473:pathology; D007121:Immunocompetence; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D014019:Tissue Donors; D016378:Tissue Transplantation / Q000009:adverse effects; D014184:Transplantation, Homologous
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens