Donor-derived leukocyte antigen class I proteins in the serum of heart transplant recipients

ArticleinThe Journal of Heart and Lung Transplantation 15(10):1012-26 · November 1996with7 Reads
Source: PubMed
Human leukocyte antigen class I proteins are expressed on most cell types in all organ allografts but are constitutively secreted only by certain organs, for example, the liver. We hypothesized that detectable levels of donor-derived human leukocyte antigen proteins would be released from transplanted cardiac allografts only when the allograft was immunologically stimulated, that is, during rejection and perhaps during viral infection. If so, then the release of donor human leukocyte antigen might be a noninvasive monitor of these events. We used an enzyme-linked immunosorbent assay to detect donor-derived human leukocyte antigen-A2 in the serum of 21 human leukocyte antigen-A2 negative recipients of human leukocyte antigen-A2-positive heart transplants. The level of donor human leukocyte antigen-A2 during the first 100 days after transplantation was correlated with the clinical status of the patient. We found little or no donor human leukocyte antigen in the serum of heart transplant recipients whose postoperative clinical course was unremarkable for infection or rejection. We did find donor-derived human leukocyte antigen in the serum of heart transplant recipients transiently in the week immediately after transplantation, continuously from patients in whom chronic rejection was developing, during cytomegalovirus infection, and during some, but not all, acute rejection episodes as determined by endomyocardial biopsy. These findings are consistent with the hypothesis that the donor human leukocyte antigen serum level reflects vascular diseases, rather than myocardial disease in the transplanted heart. Therefore, the serum level of donor human leukocyte antigen cannot be used as a monitor of cellular infiltration and myocyte damage as currently assessed by endomyocardial biopsy but may be an early indicator of the development of vascular disease such as chronic rejection.
    • "They suggest that this explains why WT mice, in the setting of pressure overload, are able to mount a robust autophagic response that is maladaptive. A more likely explanation, however, rests with the findings by Ma et al. [15] discussed earlier in the section on cardioprotection, namely, that Beclin 1 inhibits autophagic flux: (a) with less clearance there is less protection against remodeling, (b) in the Beclin 1 ?/-mice, there is less inhibition of autophagic flux; hence, there is less adverse remodeling. "
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    • "Given the impact of these cytokines on the regulation of HLA expression in parenchymal cells, we hypothesized that they could also activate the MPase, cleaving 2 m-free HC in lung cells. This could account for the increased release of sHLA during allograft rejection and for the spike of donor sHLA immediately after organ transplantation [14]. In lung allografts not undergoing acute rejection, the numbers of donor-derived leukocytes in the bronchoalveolar lavage fluid (BAL) may remain quite high: up to 60% of BAL-derived cells at 6 months post-transplant [20] . "
    [Show abstract] [Hide abstract] ABSTRACT: Activation of bronchial epithelial cells (BEC) and disruption of an intact epithelial barrier in a lung transplant recipient can lead to acute or chronic rejection, events that are associated with release of soluble human leukocyte antigen (sHLA) class I. Although we know that HLA is released from mitogen-activated lymphocytes in a metalloproteinase (MPase)-dependent fashion, the mechanism of release from nonlymphoid tissue is not well understood. To this end, we stimulated primary BEC with increasing amounts of the T-helper cell-1 cytokines, interferon gamma (IFNgamma), and/or tumor necrosis factor alpha (TNFalpha) and measured the quantity and forms of HLA class I release. We found that IFNgamma, but not TNFalpha, was able to stimulate a time- and concentration-dependent release of HLA/beta(2)m and beta(2)m-free heavy chain (HC) from the BEC. A portion (50%) of the HLA/beta(2)m release and >90% of the beta(2)m-free HC release was mediated by a MPase. Western blot analysis supported the conclusion that a MPase-sensitive pathway produced 36 and 37 kDa cleaved forms, whereas the secreted 39 kDa form of beta(2)m-associated soluble HLA class I (sHLA/beta(2)m) was MPase-resistant. This adds to the growing understanding of the extracellular processing pathways of major histocompatibility complex class I that may be critical for both chronic rejection as well as immune regulation.
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    Article · Jan 1997
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