Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression.
Alemtuzumab (CAMPATH-1H) is a depleting agent introduced recently in transplantation and often used with reduced maintenance immunosuppression. In the current study we investigated the immune response of 13 kidney allograft recipients treated with alemtuzumab followed by weaned immunosuppression with reduced dose of mycophenolate mofetil (MMF) and tacrolimus. Tacrolimus was switched to sirolimus at 6 months and MMF withdrawn at 12 months after transplantation. We found that after alemtuzumab induction the recovery of CD8(+) T cells was much faster than that of CD4(+) T cells. It was complete 6 months posttransplant while CD4(+) T cells did not fully recover even 15 months posttransplant. Repopulating CD8(+) T cells were mainly of immunosenescent CD28(-)CD8(+) phenotype. In a series of in vitro experiments we showed that CD28(-)CD8(+) T cells might suppress proliferation of CD4(+) T cells. There were three successfully treated acute rejections during the study (first at +70 day, two others +12 months) that occurred in patients with the lowest level of CD28(-)CD8(+) T cells. We hypothesize that expanded CD28(-)CD8(+) T cells might compete for 'immune space' with CD4(+) T cells suppressing their proliferation and therefore delaying CD4(+) T-cells recovery. This delay might be associated with the clinical outcome as CD4(+) T cells, notably CD4(+) T effector memory cells, were shown to be associated with rejection.
Trzonkowski
P
P
Transplantation Research Immunology Group and Oxford Transplant Centre, Nuffield Department of Surgery, University of Oxford, UK. ptrzon@amg.gda.pl
Zilvetti
M
M
Chapman
S
S
Wieckiewicz
J
J
Sutherland
A
A
Friend
P
P
Wood
K J
KJ
D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007378:Interleukins / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D007378:Interleukins; D000074323:Alemtuzumab