Expression of Soluble HLA-G Identifies Favorable Outcomes in Liver Transplant Recipients
ABSTRACT Human leukocyte antigen (HLA)-G displays immunotolerogenic properties toward the main effector cells involved in graft rejection through inhibition of natural killer cell- and cytotoxic T-lymphocyte-mediated cytolysis, and CD4 T-cell alloproliferation. An increase in serum and graft levels of HLA-G has been noted in transplant patients with improved allograft survival. However, the clinical relevance of soluble serum HLA-G molecules in tolerant pediatric and young adult liver transplant patients remains to be studied.
We examined the serum HLA-G levels in 42 pediatric and young adult liver transplant patients with a mean age of 15 years; 13 patients had operational tolerance (TOL), with complete immunosuppression withdrawal for 2.3 to 13.2 years.
Median HLA-G level in patients with acute rejection (AR) was similar to the level in pediatric healthy volunteers (9.9 vs. 4.2 U/mL, P=0.13). HLA-G was higher in patients with stable liver function on immunosuppression (54.6 U/mL) than in patients with AR (P=0.01) and healthy volunteers (P=0.003), but almost 6-fold lower than in TOL patients (325.4 U/mL). HLA-G did not correlate with clinical confounders or a history of posttransplant lymphoproliferative disease or Epstein-Barr virus; although levels in the TOL group were negatively correlated with time after immunosuppression withdrawal (r=-0.75, P=0.003). In rejectors, HLA-G levels trended to negatively correlate with a higher number (r=-0.58) and greater severity of AR episodes (r=-0.56) after 1 year posttransplantation.
Increased serum HLA-G levels track with operational tolerance of liver grafts and support favorable outcomes in pediatric and young adult recipients.
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ABSTRACT: Dendritic cells (DCs) constitute a unique set of antigen-presenting cells (APCs), equipped with the potential to initiate strong immune responses as well as to critically regulate immunity. Tolerogenic or "alternatively activated" DCs show remarkable properties in regulating immune responses both in vitro and in vivo. Furthermore, tolerogenic DCs are now beginning to be tested in clinical studies. Use of pharmacological agents to induce maturation-resistant tolerogenic DCs is a popular approach. In this review, we will discuss already recognized, as well as recently discovered, potential pharmacological agents, their mechanism of action, and the way in which they induce tolerance in DCs.International Reviews Of Immunology 12/2010; 29(6):574-607. DOI:10.3109/08830185.2010.522280 · 5.28 Impact Factor
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ABSTRACT: Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule expressed as membrane-bound and soluble isoforms. Interaction of HLA-G with its receptor, immunoglobulin-like transcript 4 on dendritic cells (DCs) down-regulates their T-cell stimulatory ability. We examined expression of HLA-G, immunoglobulin-like transcript 4, other immune regulatory molecules (inducible costimulator ligand and glucocorticoid-induced tumor necrosis factor-related receptor ligand), and the activation marker CMRF44 on circulating monocytoid dendritic cell (mDC) and plasmacytoid dendritic cell by monoclonal antibody staining and flow cytometry. Three groups of stable liver transplant recipients: operationally tolerant (TOL), prospective immunosuppressive drug weaning, and maintenance immunosuppression (MI) were studied, together with healthy controls (HC). Serum HLA-G levels were measured by enzyme-linked immunosorbent assay. In TOL patients, monocytoid dendritic cell (mDC) but not plasmacytoid dendritic cell expressed higher HLA-G than in MI patients or HC. In TOL patients, the incidence of CD4(+)CD25(hi)CD127(-) regulatory T cells (Treg) and the intensity of Treg forkhead box p3 (Foxp3) expression were significantly higher than in the MI group. HLA-G expression on circulating mDC correlated significantly with that of Foxp3 in the TOL group. There was no correlation between immunosuppressive drug (tacrolimus) dose or trough level and HLA-G expression or Treg frequency or Foxp3 expression. The incidence of patients with circulating HLA-G levels more than 100 ng/mL was highest in the TOL group, although statistical significance was not achieved. Higher HLA-G expression on circulating mDC in TOL recipients compared with MI or HC, suggests a possible role of HLA-G in immune regulation possibly mediated by enhanced host Treg Foxp3 expression.Transplantation 03/2011; 91(10):1132-40. DOI:10.1097/TP.0b013e31821414c9 · 3.78 Impact Factor
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ABSTRACT: Every liver transplant (LT) center has had patients who either self-discontinue immunosuppressive (IS) therapy or are deliberately withdrawn due to a research protocol or clinical concern (ie, lymphoproliferative disorder [LPD], overwhelming infection). This is understandable because maintenance IS therapy, particularly calcineurin inhibitors (CNI), is associated with significant cost, side effects, and considerable long-term morbidity and mortality. Detrimental effects of IS therapy include increased risk of cardiovascular disease, metabolic syndrome, bone loss, opportunistic and community-acquired infections, and malignancy. In fact, LT recipients have among the highest rates of chronic kidney disease and associated mortality among all nonkidney solid organ recipients. This mortality is only ameliorated by undergoing a curative kidney transplant, usurping costs and valuable organ resources. The search for improved treatment algorithms includes trial and error CNI dose minimization, the use of alternative IS agents (antimetabolites, mammalian target of rapamycin [mTOR] inhibitors), or even complete CNI withdrawal. Yet those who are successful in achieving such operational tolerance (no immunosuppression and normal allograft function) are considered lucky. The vast majority of recipients will fail this approach, develop acute rejection or immune-mediated hepatitis, and require resumption of IS therapy. As such, withdrawal of IS following LT is not standard-of-care, leaving clinicians to currently maintain transplant patients on IS therapy for life. Nonetheless, the long-term complications of all IS therapies highlight the need for strategies to promote immunologic or operational tolerance. Clinically applicable biomarker assays signifying the potential for tolerance as well as tolerogenic IS conditioning are invariably needed if systematic, controlled rather than "hit or miss" approaches to withdrawal are considered. This review will provide an overview of the basic mechanisms of tolerance, particularly in relation to LT, data from previous IS withdrawal protocols and biomarker studies in tolerant recipients, and a discussion on the prospect of increasing the clinical feasibility and success of withdrawal.Liver Transplantation 03/2011; 17(3):222-32. DOI:10.1002/lt.22265 · 3.79 Impact Factor