Idarubicin-145-2C11-F(ab ')2 promotes peripheral tolerance and reduces chronic vascular disease in mouse cardiac allografts
- Author(s)
- Han, WR; Murray-Segal, LJ; Gershenzon, A; Zhang, JG; Hodder, AN; Pietersz, GA; Mottram, PL;
- Details
- Publication Year 1999-12,Volume 7,Issue #4,Page 207-213
- Journal Title
- TRANSPLANT IMMUNOLOGY
- Publication Type
- Journal Article
- Abstract
- In order to reduce the toxic effects of the T cell activating anti-CD3 monoclonal antibody, 145-2C11, F(ab')2 fragments were prepared by pepsin digestion. These fragments were then used as nonimmunosuppressive carriers for the cytotoxic drug idarubicin (IDA), to reduce toxicity of both the monodonal antibodies (mAb) and the drug and to increase the specificity of drug delivery. The IDA-145-2C11 F(ab')2 immunoconjugate was tested for specificity by fluorometry. 145-2C11 intact antibody, 145-2C11 F(ab')2 and IDA conjugates of the antibody and F(ab')2 were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice with hearts surviving >100 days were challenged with donor and third party (C57BL/6) skin grafts. Although both antibody and F(ab')2 blocked the binding of 145-2C11-FITC to CBA spleen cells, only the intact antibody caused sustained depletion of CD3 cells in vivo. 145-2C11 F(ab')2 blocked cell surface CD3 within 30 min, but was cleared in 24 h without depletion of CD3 cells from the spleen. In BALB/c to CBA cardiac allografts (rejected in 12-17 days), IDA-145-2C11 F(ab')2 (0.2 mg/ 20 g mouse i.p. at the time of transplantation) induced >100 days' allograft survival and specific tolerance, in contrast to the equivalent dose of 145-2C11 F(ab')2 (mean survival 25 days). Hearts from IDA-145-2C11 F(ab')2-treated mice at >100 days showed decreased cellular infiltration and less chronic vascular disease than long-surviving hearts from mice treated with an alternative antibody, KT3. Thus, F(ab')2 prepared from 145-2C11 provided a suitable CD3-specific, nonimmunosuppressive carrier for IDA. This immunoconjugate was more effective against both acute and chronic rejection than other conjugates or whole antibody. IDA-145-2C11 F(ab')2 is an effective, nontoxic tolerogen in the mouse cardiac allograft model.
- Publisher
- ARNOLD, HODDER HEADLINE PLC
- Keywords
- VERSUS-HOST DISEASE; T-CELL RECEPTOR; MONOCLONAL-ANTIBODY; IN-VIVO; TRANSPLANTATION; INDUCTION; MODEL; MICE; IMMUNOCONJUGATE; FRAGMENTS
- Publisher's Version
- https://doi.org/10.1016/S0966-3274(99)80004-5
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 1999-12-01 12:00:00