Comparison between tacrolimus and cyclosporine as immunosuppressive agents compatible with tolerance induction by CD4/CD8 blockade.
BACKGROUND
Donor-specific tolerance can be induced in mice by transient antibody blockade of the CD4 and CD8 co-receptors of T cells. To evaluate the potential application of CD4/CD8 blockade in the clinic, we have asked if either tacrolimus or cyclosporine counteract the tolerogenic process.


METHODS
Using the fully mismatched mouse cervical heart transplant model, BALB/c (H2d) to CBA (H2k), the experimental groups were (i) no therapy, (ii) tacrolimus (1 mg/kg, i.p., daily, days 0-14); (iii) cyclosporine (25 mg/kg, i.p., daily, days 0-14), (iv) blocking monoclonal antibodies (mAbs) to CD4 and CD8 (2 mg, i.p., starting day 0 and on alternating days thereafter for a total of six doses), (v) tacrolimus plus mAbs, and (vi) cyclosporine plus mAbs.


RESULTS
Allograft survival was prolonged in both the tacrolimus and cyclosporine groups. mAbs alone induced tolerance, and mAbs combined with tacrolimus also induced tolerance. In contrast, the combination of mAbs and cyclosporine was toxic.


CONCLUSIONS
The induction of tolerance by blocking CD4 and CD8 was not prevented by tacrolimus. However, combination of cyclosporine with the same tolerogenic protocol was toxic to mice.
Moffatt
S D
SD
Department of Surgery, Addenbrooke's Hospital, Cambridge, United Kingdom.
Metcalfe
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D014019:Tissue Donors
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus