Combined donor leucocyte administration and immunosuppressive drug treatment for survival of rat heart allografts.
BACKGROUND
Donor leucocytes (DL) play an important role in rat liver transplant tolerance and their postoperative administration can convert rejection to tolerance. They appear to induce early activation, altered patterns of infiltration and death of recipient alloreactive T cells. The ability of immunosuppressive drugs to combine with DL administration was examined in a rat heart transplant model.


METHODS
Immediately after PVG to DA heterotopic heart transplantation, 6 x 10(7) spleen DL were injected. Cyclosporine A (CsA), 1.5 mg/kg/day, or methotrexate (MTX), 0.1 or 0.2 mg/kg/day, were given from day (d) 0 to d4 (early) or from d3 to d7 (delayed). Castanospermine (CAST) was administered from d0 to d7 at 100 or 300 mg/kg/day. In a separate experiment, transplanted hearts and recipient spleens were collected from treatment groups for analysis of infiltrate and cytokine mRNA expression.


RESULTS
Delayed treatment with CsA or early treatment with MTX but not CAST combined with DL to result in prolonged graft survival. Recipients treated with DL and delayed CsA had a reduced level of intra-graft interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-4R mRNA expression and reduced infiltrate compared to DL alone. Early MTX plus DL led to almost complete inhibition of all markers of inflammation during treatment followed by a rapid increase after cessation. In combination with DL, CsA was more effective than MTX for induction of donor-specific tolerance at the dose and administration regimens tested.


CONCLUSIONS
Delayed CsA or early MTX combine with DL to prolong heart allograft survival. Early and extensive inhibition of rejection by MTX was less effective than delayed and partial inhibition of the response by CsA for induction of transplant tolerance.
den Dulk
Marcel
M
AW Morrow Liver Immunobiology Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Locked Bag #6, Newtown, Sydney NSW 2042, Australia.
Wang
Chuanmin
C
Li
Jian
J
Clark
David A
DA
Hibberd
Adrian D
AD
Terpstra
Onno T
OT
McCaughan
Geoffrey W
GW
Bishop
G Alex
GA
D019264:Adoptive Transfer; D000818:Animals; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007212:Indolizines / Q000494:pharmacology*; D017708:Leukocyte Transfusion; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D011182:Postoperative Care; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D054836:Indolizidines
D016572:Cyclosporine; D016207:Cytokines; D007166:Immunosuppressive Agents; D007212:Indolizines; D008727:Methotrexate; D012333:RNA, Messenger; C037806:castanospermine; D054836:Indolizidines