Human Leukocyte Antigen-G Expression After Heart Transplantation Is Associated With a Reduced Incidence of Rejection

Abstract

Background — Human leukocyte antigen (HLA)-G, a nonclassic major histocompatibility complex class I molecule expressed in the extravillous cytotrophoblast at the feto-maternal interface, is known to protect the fetus from maternal cellular immunity. In a preliminary study, we showed that HLA-G is expressed in the hearts of some patients after heart transplantation. Methods and Results — In the present study, a larger number of patients was investigated to confirm this finding and to look for possible correlations between HLA-G expression and the number and types of rejection. Expression of HLA-G in endomyocardial biopsy specimens was investigated by immunohistochemical analysis, and detection of the soluble HLA-G in the serum was performed by immunoprecipitation followed by Western blot analysis. HLA-G was detected in the biopsy specimens and serum of 9 of 51 patients (18%). The number of episodes of acute rejection was significantly lower in HLA-G-positive patients (1.2±1.1) as compared with HLA-G-negative patients (4.5±2.8) ( P <0.001). No chronic rejection was observed in HLA-G-positive patients, whereas 15 HLA-G-negative patients had chronic rejection ( P <0.032). A longitudinal study of these patients reveals that the status of HLA-G expression was maintained after 6 months both in serum and in biopsy specimens. During this period, HLA-G-positive patients did not have chronic rejection. Conclusions — There is a significant correlation between rejection and HLA-G expression in the heart after transplantation. HLA-G expression and its effect in reducing the incidence and severity of rejection seem to be stable throughout the evolution.

Alloreactive CD4+ and CD8+ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

“…In the context of human allotransplantation, these HLA-G molecules have been detected in graft biopsies and sera from patients who had undergone heart or kidney/ liver transplantation [4][5][6][7]. In these cases, HLA-G was associated with allograft acceptance, suggesting that titration of seric soluble HLA-G levels may be useful for monitoring the clinical course of allotransplantation [8].…”

“…Nevertheless, these drugs have serious side effects and further investigations of alternative immunotolerant strategies are sought [3]. Recently, nonclassical HLA class I molecule HLA-G, which is a wellknown tolerogeneic molecule, was found to contribute to allograft acceptance in transplanted patients [4][5][6][7][8].…”

“…In human allo-transplantation, ectopic HLA-G expression was demonstrated in graft biopsies and sera from heart-or kidney/liver-transplanted patients who exhibit a better graft acceptance [4,5,7]. However, the cells and mechanisms involved in such a de novo expression of HLA-G remain unknown.…”

Soluble HLA-G: Are they clinically relevant?

“…Studies carried out in transplant recipients have made the following observations: i) in renal allograft recipients, the presence of serum sHLA-G is positively correlated with functioning transplants [52], ii) heart transplanted patients displaying a significant increase in serum sHLA-G in the first month after transplantation have a lower incidence of severe rejection episodes than patients with low levels of the molecule [53], and iii) in liver transplanted patients, high serum levels of sHLA-G showed a positive correlation with normal liver function tests, whereas a fall in sHLA-G levels was rapidly followed by deterioration of liver functional parameters [25,54].…”

Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites

“…3 It must be noted that, in these cases, expression of HLA-G was detected in situ in cells that are the primary targets of the immune system, e.g endomyocardial cells in heart grafts, 11,37 biliary epithelial cells in liver transplants , 12 and tubular epithelial cells after kidney transplantation. 35 Despite the large amount of information concerning HLA-G expression in solid organ transplantation, there have been no similar studies in the allogeneic hematopoietic cell transplantation (allo-HCT) setting.…”