Immunological effects of the anti-IL-2 receptor monoclonal antibody BT 563 in liver allografted patients.
The immunological effects of therapeutic monoclonal antibodies (mAbs) depend upon their interaction with the target structure as well as the isotype of the mAb which is responsible for the binding to Fc receptors of accessory cells. The aim of the presented analysis was the evaluation of the in vivo immunosuppressive effect of BT 563, a mAb directed to the alpha-chain of the interleukin-2 receptor (IL-2R). Thirty-eight patients following liver transplantation were treated prophylactically for 12 days with 10 mg/day BT 563 (clinical phase II and III study). As baseline immunosuppression cyclosporin (CyA) and low dose steroids were administered. BT 563 levels, lymphocyte subpopulations, levels of soluble CD25 and Fc receptor polymorphism were evaluated and compared to the clinical outcome. Preoperatively in all patients a small subset of CD45R0+ cells expressed CD25 with detectable density. These cells were coated by BT 563. There was no evidence for depletion of IL-2R+ cells or modulation of the IL-2R. During therapy stable levels of the soluble IL-2R were measured in patient sera. Throughout the therapy high levels of unbound BT 563 were found in sera, suggesting that IL-2R newly expressed on cells activated by the allograft could also be inhibited by BT 563. No acute rejections were observed in these patients and no side effects of BT 563 were noted. There were only minor bacterial infections, while mycotic or viral infections did not appear. Administration of BT 563 together with CyA and low dose steroids to liver allografted patients represents a safe and effective protocol. Its action is likely to be mediated by turning off the pathway of signal transduction of the IL-2R in T-cells by the antibody while IL-2 gene transcription is simultaneously modified by CyA and steroids. The addition of all three immunosuppressive mechanisms is suggested to lead to a state of anergy during mAb application that is reversible at the end of antibody therapy but does not lead to rebound rejections. Analysis of the phenotype of CD25+ cells showed that they preferentially belonged to the CD45R0+ cell type. Thus we assume that BT 563 specifically turns off preactivated cells enabling rather selective and effective immunoprophylaxis in liver allografted patients.
Nashan
B
B
Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany.
Schwinzer
R
R
Schlitt
H J
HJ
Wonigeit
K
K
Pichlmayr
R
R
D000911:Antibodies, Monoclonal / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D016031:Liver Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000145:classification; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D017452:Receptors, IgG / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D013491:Suppressor Factors, Immunologic / Q000097:blood / Q000494:pharmacology*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; D013491:Suppressor Factors, Immunologic