Regulation of skin and islet allograft survival in mice treated with costimulation blockade is mediated by different CD4+ cell subsets and different mechanisms.
BACKGROUND
Donor-specific transfusion (DST) and a brief course of anti-CD154 monoclonal antibody (mAb) induces permanent islet and prolonged skin allograft survival in mice. Induction of skin allograft survival requires the presence of CD4 cells and deletion of alloreactive CD8 cells. The specific roles of CD4 and CD4CD25 cells and the mechanism(s) by which they act are not fully understood.


METHODS
We used skin and islet allografts, a CD8 T cell receptor (TCR) transgenic model system, and in vivo depleting antibodies to analyze the role of CD4 cell subsets in regulating allograft survival in mice treated with DST and anti-CD154 mAb.


RESULTS
Deletion of CD4 or CD25 cells during costimulation blockade induced rapid rejection of skin but only minimally shortened islet allograft survival. Deletion of CD4 or CD25 cells had no effect upon survival of healed-in islet allografts, and CD25 cell deletion had no effect upon healed-in skin allograft survival. In the TCR transgenic model, DST plus anti-CD154 mAb treatment deleted alloreactive CD8 T cells, and anti-CD4 mAb treatment prevented that deletion. In contrast, injection of anti-CD25 mAb did not prevent alloreactive CD8 T cell deletion.


CONCLUSIONS
These data document that (1) both CD4CD25 and CD4CD25 cells are required for induction of skin allograft survival, (2) CD4CD25 T cells are not required for alloreactive CD8 T cell deletion, and (3) CD4CD25 regulatory cells are not critical for islet allograft tolerance. It appears that skin and islet transplantation tolerance are mediated by different CD4 cell subsets and different mechanisms.
Banuelos
Scott J
SJ
Department of Surgery, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Markees
Thomas G
TG
Phillips
Nancy E
NE
Appel
Michael C
MC
Cuthbert
Amy
A
Leif
Jean
J
Mordes
John P
JP
Shultz
Leonard D
LD
Rossini
Aldo A
AA
Greiner
Dale L
DL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001803:Blood Transfusion; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D007165:Immunosuppression Therapy / Q000379:methods; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D023421:Models, Animal; D016038:Skin Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand