Brief cyclosporine treatment prevents intrathymic (IT) tolerance induction and precipitates acute rejection in an IT rat cardiac allograft model.
BACKGROUND
Intrathymic (IT) alloantigen combined with administration of rabbit anti-rat anti-lymphocyte serum (ALS) intraperitoneally induces donor-specific tolerance to rat cardiac transplants. The purpose of this study was to examine the effect of a brief course (4 days) of cyclosporine (CsA) on the development of IT tolerance.


METHODS
Buffalo (BUF) (RT1b) rats were given 25x10(6) fully MHC-mismatched Lewis (LEW) (RT1l) splenocytes by IT injection plus 1.0 ml of ALS intraperitoneally. Twenty-one days later, IT donor-specific LEW (group 1) or third-party (ACI, RT1a) (group 2) hearts were heterotopically transplanted to the abdominal aorta A third group of BUF (group 3) were given daily CsA (10 mg/kg) by oral gavage for 4 days before administration of IT LEW cells and ALS. Rejection as defined by the cessation of a palpable heartbeat was confirmed by histology. Cytokine profiles of allografts from all groups were then analyzed using a multi-probe RNase protection assay.


RESULTS
Sixty-seven percent of IT/ALS-treated BUF recipients not pretreated with CsA accepted LEW heart grafts for greater than 90 days. However, 86% of animals treated with CsA for 4 days before IT injection and ALS rejected allografts at 10.7+/-3.2 days. Third-party allografts (ACI) were uniformly rejected (7.0+/-0.0 days). Histology confirmed cellular rejection in CsA-treated allografts and cytokine analysis detected increased interleukin (IL)-3, IL-5, and tumor necrosis factor-alpha when compared to increased IL-2 and interferon-gamma in rejecting untreated controls.


CONCLUSIONS
CsA can prevent the induction of intrathymic alloantigen tolerance. These results support the development of a CsA-sensitive, but IL-2-independent, active regulatory mechanism after intrathymic exposure to donor-specific alloantigen and depletion of mature peripheral T cells.
Smith
C R
CR
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Mohanakumar
T
T
Shimizu
Y
Y
Yu
S
S
Otomo
N
N
Kaleem
Z
Z
Flye
M W
MW
D000818:Animals; D002452:Cell Count / Q000187:drug effects; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008955:Models, Cardiovascular; D051381:Rats; D011912:Rats, Inbred ACI; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology; D013950:Thymus Gland / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine