Evidence that an anthracycline-anti-CD8 immunoconjugate, idarubicin-anti-Ly-2.1, prolongs heart allograft survival in mice.
To examine the potential use of immunoconjugates of drugs and antibodies as immunosuppressive agents, mice were treated with a short course (4 days) of T-cell-specific anti-Ly-2.1 monoclonal antibody, or MAB conjugated to an anthracycline, idarubicin (IDA). The anti-Ly-2.1 MAB had no significant effect on the survival of BALB/c (Ly-2.2) heart allografts in CBA (Ly-2.1) mice, but was a potent immunosuppressive agent when coupled to IDA, with most grafts surviving for > 100 days following treatment with doses ranging from 10 to 120 micrograms IDA, covalently coupled to 1-8 mg MAB. IDA-MAB treated mice with long-surviving heart grafts showed donor-specific tolerance. They did not reject donor-type skin grafts (these survived for > 50 days), but rejected third-party skin in 10-14 days. Heart allografts in these mice survived for > 100 days. Allografts placed 30 days after treatment were rejected, showing a recovery of peripheral T cell function at this time. Newly derived thymic T cells were, however, not required for this recovery since adult thymectomized, IDA-MAB treated animals also recovered T cell function and rejected heart allografts. FACScan analysis of T cells from mice treated with 80 micrograms IDA-4 mg MAB, which had received a heart allograft, showed 95% T cell depletion in the spleen compared with ungrafted, IDA-MAB treated animals, and untreated controls with or without allografts. Splenic T cell depletion was however not significant in CBA mice immunosuppressed with the lower dose of 10 micrograms IDA-MAB. Thus rapid depletion of splenic T cells was not required for immunosuppression induced by IDA-MAB conjugates. However, the minor subpopulation of Ly-2+, which was activated by alloantigen while carrying IDA-MAB, may be depleted during the T cell response to the allograft, resulting in a state of alloantigen-specific tolerance in mice with long-surviving heart allografts.
Mottram
P L
PL
Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia.
Pietersz
G A
GA
Smyth
M J
MJ
Purcell
L J
LJ
Clunie
G J
GJ
McKenzie
I F
IF
D000818:Animals; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly / Q000276:immunology*; D001012:Aorta, Abdominal; D016827:CD8 Antigens / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D015255:Idarubicin / Q000276:immunology*; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014683:Vena Cava, Superior
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D016827:CD8 Antigens; D000922:Immunotoxins; D015255:Idarubicin