Analysis of primate renal allografts after T-cell depletion with anti-CD3-CRM9.
BACKGROUND
FN18-CRM9 is a CD3-specific immunotoxin that is capable of depleting CD3+ T cells. Pretreatment of rhesus monkeys with this agent before transplantation can induce donor-specific tolerance and "split tolerance" to renal allografts.


METHODS
Heterotopic renal transplants were performed on monkeys that received posttransplant FN18-CRM9. Histological and immunohistological staining, as well as analysis of the intragraft cytokine profile by reverse transcriptase polymerase chain reaction, was performed on percutaneous allograft biopsies.


RESULTS
Experimental monkeys had significant prolongation of allograft survival. Although an interstitial, mononuclear cell infiltrate was seen in all of the renal transplants, there was minimal evidence of acute cellular rejection. Histological evidence of alloantibody-mediated damage was detected 3 to 5 months after transplantation in the monkeys treated with FN18-CRM9. Immunohistology demonstrated the reappearance of CD3+ and CD4+ T cells, as well as CD20+ B cells, in the grafts. Cytokine analysis demonstrated expression of interferon-gamma. An intact anti-donor IgG response was seen.


CONCLUSIONS
Treatment of monkeys with FN18-CRM9 immediately after transplantation significantly prolongs renal allograft survival. Allograft biopsies demonstrate a lack of acute cellular rejection; however, alloantibody-mediated graft damage and rejection occur, with an intact anti-donor IgG response. The intragraft expression of the interferon-gamma may reflect this ongoing humoral rejection. These data suggest that even a brief period of T-cell allosensitization may lead to humorally mediated allograft damage. Efforts to achieve tolerance with posttransplant FN18-CRM9 will require modification of the protocol to deplete T cells before allosensitization exposure or to supplement the posttransplant immunomodification strategy.
Department of Surgery, University of Wisconsin, Madison 53792, USA.
N
N
Armstrong
P
P
Buckley
T
T
Oberley
J
J
Fechner
Y
Y
Dong
X
X
Hong
A
A
Kirk
D
D
Neville
S
S
Knechtle
D000818:Animals; D017252:CD3 Complex / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006085:Graft Survival / Q000502:physiology; D007074:Immunoglobulin G / Q000032:analysis; D000922:Immunotoxins / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion / Q000379:methods*; D008253:Macaca mulatta / Q000502:physiology*; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D017252:CD3 Complex; D016207:Cytokines; D007074:Immunoglobulin G; D000922:Immunotoxins