Donor-Specific Antibodies in Allograft Rejection: Clinical and Experimental Data

Abstract

The ability of donor-specific major histocompatibility complex alloantibodies to destroy a transplanted organ within minutes, the so-called hyperacute rejection phenomenon, has been known for a long time. It is a clear demonstration of the possible cytotoxic effect of antibodies. Apart from this particular situation, the role of antibodies in inducing acute or chronic allograft rejection remains controversial. Many clinical data have shown that transplant recipients capable of developing class I or class II anti-HLA antibodies experienced shorter survival periods than those who were not. This fact, in accordance with experimental data, only demonstrates that high antibody responders reject a transplant more easily than low responders. More interestingly, there is now increasing evidence that posttransplant appearance of donor-specific alloantibodies, and probably of alloreactive-induced autoantibodies, is strongly correlated with reduced graft survival rate, especially from chronic rejection. We demonstrated that donor-specific HLA antibodies can be found in more than 70% of transplanted kidneys with chronic allograft nephropathy, and that the intragraft presence of such antibodies is significantly correlated with high numbers of plasma cells on early biopsies and C4d deposits, a recognized marker of humoral rejection. It is likely that non-HLA antibodies also play a deleterious role in organ transplant outcome, particularly the heterogeneous group of anti-endothelial cells antibodies, anti-MIC antibodies, autoantibodies and some others with no recognized target. Convincing experimental data, especially using B cell and T cell deficient mice, strongly suggest that B cells and donor-specific antibodies are required for fully developed chronic allograft rejection. The role of antibodies in inducing the cascade of cytokines and growth factors leading to tissue lesions is of increasing interest since it is now possible to control B cell proliferation and antibody production.

How Can We Measure Immunologic Tolerance in Humans?

“…Initially, studies that examined the role of antidonor HLA-specific antibodies on outcomes of renal transplantation focused primarily on the pretransplantation setting with the aim of avoiding hyperacute or early antibody-mediated rejection. However, it also is clear that the de novo development of antidonor HLA antibodies after transplantation has deleterious effects on renal allograft survival (56). Given this correlation, efforts to develop methods to inhibit or reverse the formation of new donor-specific antibodies after transplantation are likely to be informative and important.…”

Antibody to human leukocyte antigen triggers endothelial exocytosis

“…Many of these patients have had transfusions of blood products, pregnancy, or previous transplants that result in the production of antibody to HLA and the formation of memory B cells (1,2). Transplanted patients with antibodies to HLA have increased rejection episodes and respond poorly to conventional immunosuppression (2)(3)(4)(5). Recent clinical studies suggest that antibodies play a key role in the majority of irreversible acute rejections (6).…”

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

“…The first involves alloantibodies binding to donor vascular endothelium, resulting in Ab-mediated vascular rejection via complement activation and ligation of FcRs (26) leading to graft thrombosis. Clinical studies by Rifle et al and others have demonstrated that the presence of high titers of preformed alloantibodies in transplant recipients correlates with complement deposition and poor graft survival (27,28). Rodent studies have demonstrated that the transfer of subthreshold doses of complement-activating Abs into B cell-deficient recipients (C57BL/6 Ig Ϫ/Ϫ ) receiving B10.A (H-2 a ) cardiac allografts restored acute humoral rejection, while the inhibition of the terminal complement activation with anti-C5 mAbs prevented Ab-mediated rejection, leading to long-term graft survival and accommodation (29).…”