Antibody-mediated Rejection Without Acute Graft Dysfunction in Adult ABO-compatible Heart Transplantation: a Case of Accommodation Annalisa Angelini, MD, a Chiara Castellani, BSc, PhD, a Francesca Poli, MD, b Elena Benazzi, MD, b Gianluca Torregrossa, MD, c Francesco Tona, MD, PhD, c Antonio Gambino, MD, c Alida P. Caforio, MD, PhD, c Giuseppe Feltrin, MD, PhD, c Giuseppe Toscano, MD, c Marialuisa Valente, MD, a Gaetano Thiene, MD, a and Gino Gerosa, MD c Humoral rejection in heart transplantation is associated with graft dysfunction, circulating anti-donor antibodies and C4d deposits in endomyocardial biopsies. Detecting C4d capillary positivity is of diagnostic and prognostic value. C4d positivity can be found in solid-organ transplants in cases of “accommodation,” a form of humoral rejection without graft dysfunction. Accommodation might reflect a change in antibodies or in the antigen, or the graft acquiring a resistance to injury by antibodies and complement. We present a case of accommodation in the setting of adult ABO-compatible orthotopic heart transplantation, which was diagnosed according to the recently introduced ISHLT criteria for humoral rejection: despite this immunologic profile, the patient never showed signs of graft dysfunction. Physicians should be aware of the accommodation phenomenon so they can identify this subset of patients and assess its long-term effects on chronic rejection and outcome in transplanted patients. J Heart Lung Transplant 2008;27:1357– 60. Copyright © 2008 by the International Society for Heart and Lung Transplantation. Antibody-mediated rejection in cardiac transplantation is diagnosed in the setting of graft dysfunction, circulating anti-donor antibodies and C4d deposits in endomyocardial biopsies. The detection of C4d capillary positivity serves as a valuable diagnostic and prognostic marker. 1– 6 C4d positivity can be found in organ transplants in cases of “accommodation,” a phenomenon discovered in the course of ABO-incompatible renal transplants that seemed to function perfectly well despite anti– blood group anti- bodies in the blood of recipients. 7,8 As a successful engraftment mechanism, accommodation is thought to result from the graft acquiring a resistance to humoral injury, and accumulating evidence suggests that it can be induced by bound anti-donor antibodies and complement. Accommodation must be differentiated by transplant tolerance. The precise definition of transplant toler- ance, often discussed but rarely agreed upon, is consid- ered to be the lack of a destructive immune response toward the graft in the absence of ongoing immunosup- pressive therapy. 6 This is manifested clinically by nor- mal graft function in the absence of acute and chronic rejection. However, implicit in this definition is that such a state must co-exist with general immune com- petence, including normal immune responses to patho- gens and cancer risks no different than the general population. We report an unusual case of cardiac allograft hu- moral rejection in a young adult patient with a compli- cated post-operative course, who did not develop heart dysfunction. This may be considered a case of accom- modation in an ABO-compatible orthotopic heart trans- plant. Accommodation reflects a biologic change, or a coordinated series of changes, enabling cells and tissues to withstand noxious agonists, cells or other factors directed against them. As a mechanism of successful engraftment, it must be distinguished from tolerance, in which the immune response to a graft is selectively abrogated, resulting in a generalized unresponsive- ness. 9 Based on findings in xenograft accommodation, which might also apply to non-xenograft accommoda- tion, this phenomenon can be explained by three factors: the development of “protective genes,” such as heme oxygenase 1, A20, bcl-2 and bcl-x, which could block nuclear factor-kappaB (NF-B) activation and thus From the a Department of Medical-Diagnostic Sciences and Special Therapies, University of Padua Medical School, Padua, Italy; b Depart- ment of Regenerative Medicine Transplant Immunology, IRCCS OMP MARE, Milan, Italy; and Departments of c Cardiology and Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy. Submitted June 27, 2008; revised August 25, 2008; accepted September 3, 2008. Reprint requests: Annalisa Angelini, MD, Department of Medical- Diagnostic Sciences and Special Therapies, Pathological Anatomy– Cardiovascular Pathology, University of Padua Medical School, Via A. Gabelli 61, 35121 Padova, Italy. Telephone: +39-049-8272260. Fax: +39-049-8272205. E-mail: annalisa.angelini@unipd.it Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.09.004 1357