Anti-Skeletal Muscle Glycolipid Antibodies in Human Heart Transplantation as Predictors of Acute Rejection

Abstract

In forty-five patients who underwent orthotopic heart transplantation, the titer of anti-human skeletal muscle glycolipid antibodies (AGA) present in the sera at the moment of transplantation was correlated with the number of histologically diagnosed cellular grade 3A and humoral acute rejection episodes during the first 120 days after transplantation. Determination of a cutoff value of 0.800 for the AGA level was determined by a receiver operating characteristic curve. Thirteen of 19 patients (68.4%) with an AGA titer above 0.800 developed 24 severe rejection episodes, and of the 26 patients with an AGA titer below 0.800, only 4 (15.3%) presented 6 severe rejection episodes during that time. This was especially evident for the humoral rejection episodes, which were diagnosed in only 1 of the 26 patients with AGA below 0.800 and in 7 of the 19 with AGA above 0.800. Comparison by univariate analysis of other well-known risk factors for a greater number of rejection episodes during the early posttransplant period with the AGA level at the moment of transplantation revealed that the latter distinguished a greater number of patients at risk than the other factors, such as a female donor, the lymphocyte direct cross-match, or the status of the patients at transplantation; the odds ratios were 6.33 for the AGA level, 3.17 for the direct cross-match, and 2.76 for the status at transplantation. By multiple logistic regression analysis, the only relevant risk factors in our group of patients were the AGA level (P=0.0009) and the status at transplantation (P=0.0285). These results indicate that determination of the AGA level at the moment of transplantation could represent a useful method for distinguishing which patients are at risk for a greater number of rejection episodes during the early posttransplant period, with a greater sensitivity than other risk factors.

Autoimmune Sensitization to Cardiac Myosin Leads to Acute Rejection of Cardiac Allografts in Miniature Swine

“…Most importantly, Warraich et al (13) recently reported the presence of anti-CM autoantibodies during acute rejection of cardiac allografts in patients with dilated cardiomyopathy. Recently, the presence of autoimmune responses to CM has been observed in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy (10, 12). Therefore, autoimmunity to CM represents a general phenomenon in cardiac allotransplantation.…”

“…Most importantly, tolerance induction to CM and collagen type V has been shown to significantly prolong the survival of heart and lung transplants, respectively (8, 9). Finally, several studies have provided evidence suggesting the relevance of CM autoimmunity in clinical cardiac transplantation (10–13). Collectively, these studies suggest that secondary immunity to tissue-specific antigens may represent an essential component of allograft rejection.…”

Antibodies Reactive to Non-HLA Antigens in Transplant Glomerulopathy

“…12 Mounting associative evidence suggests that such pretransplant autoimmunity to myosin, among other antigens, contributes to post-transplant graft injury. 13,14 In addition to pre-existing autoimmunity, ischemia reperfusion injury and tissue healing necessitated by transplant surgery, along with anti-donor alloimmunity, result in inflammation [15][16][17][18] and ex-posure of cryptic or sequestered self-antigens to the immune system. 19 -21 These processes overcome self-tolerance, resulting in de novo pathogenic autoimmunity.…”

Humoral autoimmunity after solid organ transplantation: Germinal ideas may not be natural

“…By the early 2000s, studies had begun to use ELISA or cDNA libraries to identify more precisely the self-antigens targeted by humoral autoimmunity (20)(21)(22)(23)(24)(25)(26). These studies often revealed that the target autoantigens were expressed specifically in the donor organ, for example: vimentin intermediate filament (24), myosin motor protein (23,25), and skeletal muscle glycolipid (21) following heart transplantation; glutamic acid decarboxylase (GAD) enzyme and islet antigens following pancreas transplantation (22); and glomerular basement membrane protein agrin in renal transplant recipients (20), with the latter study by Joosten et al demonstrating a strong correlation with anti-agrin autoantibody and the development of transplant glomerulopathy. That graft-specific autoantigen was frequently identified as a target of TAA supports a contributory role for autoantibody in graft rejection, but it should be noted that this apparent focus may simply reflect the deliberate selection of graft-related autoantigens for capture in ELISA; use of cDNA libraries suggested a broader humoral autoimmune response (26).…”