Split tolerance induced by immunotoxin in a rhesus kidney allograft model.
BACKGROUND
Renal allografts were performed in rhesus monkeys using FN18-CRM9, a potent immunotoxin capable of depleting T cells to less than 1% of baseline levels in blood and lymph nodes, as a preparative agent. We have recently reported that animals pretreated with FN18-CRM9 1 week before transplantation without further immunosuppression had prolonged graft survival time compared with control animals, and frequently became tolerant.


METHODS
This report examines the alloimmune responses of recipient monkeys to the donor, including cytotoxic T lymphocyte precursor (CTLp) frequency, mixed lymphocyte response, and antidonor IgG response.


RESULTS
CTLp frequencies declined significantly (P<0.01) after FN18-CRM9 treatment and renal transplantation. This decline in CTLp was initially nonspecific, as CTLp frequencies against third-party animals also declined (P<0.01). The decrease in CTLp was maintained in five of five animals tested 6 months after transplant. However, unresponsiveness was limited to the CTL arm of the immune response as antidonor IgG was detected in four of four animals tested, and the 5-day mixed lymphocyte response stimulation index and relative response were not significantly different before and after transplant. In long-term survivors (>150 days), an increase in anti-third-party CTLp was detected 1 month after grafting with third-party skin. No change was seen in the antidonor CTLp frequency after donor skin grafting, indicating that a specific defect in the antidonor CTL response had developed.


CONCLUSIONS
These data suggest that FN18-CRM9 treatment of rhesus monkeys allows the development of specific down-regulation of antidonor CTL activity in renal allograft recipients.
Fechner
J H
JH
Department of Surgery, University of Wisconsin, Madison 53792, USA.
Vargo
D J
DJ
Geissler
E K
EK
Graeb
C
C
Wang
J
J
Hanaway
M J
MJ
Watkins
D I
DI
Piekarczyk
M
M
Neville
D M
DM
Knechtle
S J
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001426:Bacterial Proteins / Q000494:pharmacology*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D000922:Immunotoxins / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008253:Macaca mulatta; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; C053395:CRM9 protein, bacteria; D004167:Diphtheria Toxin; D007074:Immunoglobulin G; D000922:Immunotoxins