title: Post-transplant therapy with high-dose intravenous gammaglobulin: Applications to treatment of antibody-mediated rejection.
abstract: B-cells and their products (antibodies) are now recognized as important mediators of allograft rejection. This represents a significant departure from previous doctrine where the T-cells were felt to be of paramount importance. Antibody-mediated rejection (AMR) has emerged as a significant and common complication of transplantation. The development of donor-specific (anti-HLA class I and class II) antibodies is known to correlate strongly with the development of AMR. Recognition of the unique features of AMR that were often confused with non-specific acute tubular injury is aided considerably by improvements in monitoring of anti-HLA antibodies and the immunopathologic demonstration of C4d staining in affected capillary beds. Although imperfect, the demonstration of C4d (a complement breakdown product) staining in an allograft, especially accompanied by the presence of anti-HLA antibodies in the recipient sera, strongly suggests a diagnosis of AMR. Thus, AMR is a complement-dependent, antibody-mediated disorder. AMR can occur as a de novo complication of transplantation in individuals not previously recognized to be sensitized to HLA antigens, but more often occurs as a complication of desensitization therapies in highly-HLA sensitized patients. AMR may also constitute a significant portion of what is now referred to as chronic allograft nephropathy (CAN). The prognosis of C4d (+) AMR is poor as current therapies for treatment of AR are directed primarily at the T-cell. Until recently, no therapeutic options existed to address this problem from a primary etiological standpoint. Here we discuss the use of high dose IVIG as an option for treatment of AMR. We have significant experience with this approach which is outlined here. IVIG has many ideal advantages as a therapy for AMR. First, it can down regulate B-cell activation and antibody production, second, it can induce anti-inflammatory cytokines and contains blocking antiidiotyic antibodies to anti-HLA antibodies and third, IVIG has the unique ability to block complement-mediated injury through inhibition of C3 activation. Further clinical trials are necessary to prove efficacy for treatment of AMR.
authors.affiliation: Renal Transplant Program, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA. sjordan@cshs.org
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Vo
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
authors.forename: Dolly
authors.initials: D
authors.lastname: Tyan
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
mesh_terms: D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D002985:Clinical Protocols; D003176:Complement C3 / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003888:Desensitization, Immunologic; D015536:Down-Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology
chemical_list: D003176:Complement C3; D016756:Immunoglobulins, Intravenous