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
Abstract
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. "
    [Show abstract] [Hide abstract] ABSTRACT: Whether an element of routine housekeeping or in the setting of imminent disaster, it is a good idea to get one's affairs in order. Autophagy, the process of recycling organelles and protein aggregates, is a basal homeostatic process and an evolutionarily conserved response to starvation and other forms of metabolic stress. Our understanding of the role of autophagy in the heart is changing rapidly as new information becomes available. This review examines the role of autophagy in the heart in the setting of cardioprotection, hypertrophy, and heart failure. Contradictory findings are reconciled in light of recent developments. The preponderance of evidence favors a beneficial role for autophagy in the heart under most conditions.
    Full-text · Article · Nov 2012
    • "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.
    Full-text · Article · Oct 2002
  • [Show abstract] [Hide abstract] ABSTRACT: The light chain of HLA class I protein (beta 2m) has been expressed in Aspergillus nidulans. The cDNA of beta 2m was modified using the polymerase chain reaction to include overlapping extensions for its subsequent fusion into an Aspergillus vector. This fusion resulted in beta 2m cDNA being flanked by the Aspergillus awamori glucoamylase promoter and the Aspergillus niger glucoamylase terminator. Expression of beta 2m was induced by the addition of starch to the culture medium. In preliminary mass culture trials, 177 micrograms/liter of f beta 2m were obtained in 60-liter fermentations. N-terminal sequencing of purified human beta 2m produced in fungi (f beta 2m) revealed that 28% of the purified protein was of proper sequence and 61% of the protein had an additional serine and lysine residue derived from the C-terminus of the fungal leader. Purified f beta 2m from culture supernatants appeared biochemically similar to beta 2m obtained from human urine (u beta 2m) as seen in immunoblot analysis. Functionally, f beta 2m effectively interacted as a subunit of class I MHC molecules. This was seen both in a sandwich ELISA for detecting properly folded HLA class I heavy chain and in assays showing cell-surface beta 2m exchange into the mouse class I MHC H-2Kd. In these experiments the biological activity of f beta 2m was indistinguishable from u beta 2m. The successful expression of biologically active beta 2m in A. nidulans suggests that fungal systems might be useful for the production of other active components of the HLA class I MHC complex.
    Article · Jan 1997
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