Correlation of donor-specific antibodies, complement and its regulators with graft dysfunction in cardiac antibody-mediated rejection.

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d- group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d- group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d- patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.

Transplantation immunology.

The practice of clinical and experimental transplantation continues to evolve at a rapid pace. To appreciate the current transplant practices, it is first necessary to review transplant immunology in its proper context, ie, as a component of the complex series of events that promote the repair of damaged tissues. These processes are generally categorized as inflammation, immunity, and tissue repair/reinforcement. In general, there are 3 forms of graft rejection: hyperacute, acute, and chronic rejection. All 3 forms of graft rejection represent pathologic consequences of one or more of these repair-related processes. The various graft rejection responses also illustrate several complex immunologic principles that need to be considered. These include the definition of an alloantigen, the structure and function of major histocompatibility complex molecules, and the behavior of antigen-presenting cells and alloreactive T cells. This review combines these concepts and principles into a discussion of the 3 forms of graft rejection, each of which is addressed at the level of histopathology, pathobiology, incidence, and clinical strategies.

In vitro stimulation of human endothelial cells by sera from a subpopulation of high-percentage panel-reactive antibody patients.

We have studied a serum activity that enhances in vitro ICAM-1 expression by human endothelial cells (EC) and report that this activity can be found in approximately 8% of pretransplant serum samples from individuals with a history of high %PRA. Hence, most high %PRA sera lack this activity, and, furthermore, mixing these negative sera does not result in an active serum pool. In patients with active serum, the ICAM-1 enhancing activity is found only sporadically, despite the continuous detection of endothelial-reactive antibodies. Absorption of Ig from a high %PRA serum reduced ICAM-1 enhancing activity, as well as endothelial-reactive antibodies. However, enhancing activity can sometimes be observed in sera that lack detectable endothelial-reactive antibodies, and none of several patient sera with defined MHC class I-specific alloantibodies displayed ICAM-1 enhancing activity. Together, these data suggest that ICAM-1 enhancing activity may not necessarily be mediated by anti-MHC alloantibodies. In addition to influencing this expression, ICAM-1 active patient sera also influence EC expression of VCAM-1 and MHC class I, but not MHC class II molecules, a pattern that is similar to that stimulated by TNF alpha. However, coincubation of EC with active serum plus soluble TNF receptor did not block the endothelial phenotypic changes, despite the ability of the soluble receptor to completely abrogate endothelial changes induced by TNF alpha. IFN gamma also increases endothelial ICAM-1 expression, but has response kinetics different from that of active serum. Interestingly, brief treatment of endothelial cells with IFN gamma greatly increased the amount of IgG bound from the active sera by EC. We conclude that some pretransplant patients occasionally express an activity in their serum that influences EC expression of several adhesion molecules, including ICAM-1, VCAM-1, and MHC class I. This activity may be associated with alloantibodies, but is independent of MHC class I-reactive antibodies, circulating TNF alpha, or IFN gamma. The relevance of a serum-borne component capable of activating EC is discussed.