Regulatory functions of alloreactive Th2 clones in human renal transplant recipients.
BACKGROUND
Chronic allograft rejection is the major clinical problem in organ transplantation. There is evidence that indirect T cell recognition of donor-specific HLA peptides may play an important role in the immunopathogenesis of chronic allograft rejection. We have recently shown that HLA allopeptide-specific T cell clones generated from renal transplant recipients with chronic allograft nephropathy are of the Th1 phenotype, while those from stable patients are Th2. There is evidence in experimental animal models of autoimmunity and transplantation that Th2 cells may function to regulate immune responses, but the biological relevance of these observations in humans has not been reported.


METHODS
The purpose of this study was to investigate the putative regulatory functions of alloreactive human Th2 clones. HLA-DR allopeptide-specific Th1 and Th2 cell clones were generated from peripheral blood lymphocytes of human renal allograft recipients with chronic allograft nephropathy (CAN) or with stable renal function (SRF), respectively.


RESULTS
An in vitro co-culture system showed that the proliferative responses of Th1 clones from patients with CAN were significantly inhibited by the Th2 clones in response to the donor-derived HLA allopeptides. In addition, co-culture of the Th2 clones inhibited cytokine production (IFN-gamma) by the Th1 clones in response to the donor-specific peptides. The regulatory functions of Th2 clones were antigen-specific since they only occurred when both the Th1 and Th2 clones were reactive to the same HLA-DR allopeptide, and were mediated by IL-4 and IL-10.


CONCLUSIONS
This is the first demonstration, to our knowledge, indicating that Th2 cells may function to regulate indirect Th1 alloimmune responses that are critical for the progression of CAN in humans.
Kist-van Holthe
Joana E
JE
Division of Nephrology, Children's Hospital, and Renal Division, Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Gasser
Martin
M
Womer
Karl
K
Najafian
Nader
N
Dong
Victor
V
Samsonov
Dimitry V
DV
Geehan
Chris S
CS
Chandraker
Anil
A
Sayegh
Mohamed H
MH
Waaga
Ana Maria
AM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002908:Chronic Disease; D002999:Clone Cells; D006084:Graft Rejection / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D006684:HLA-DR Antigens; D016753:Interleukin-10; D015847:Interleukin-4