Association Between HLA-G Expression and C4d Staining in Cardiac Transplantation

Sheshgiri, Rohit; Rao, Vivek; Mociornita, A.G.; Ross, Heather J.; Delgado, Delgado H.

doi:10.1097/tp.0b013e3181ca88d5

Cited by 12 publications

(8 citation statements)

References 6 publications

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“…An interesting finding was the significantly lower proportion of patients with Luminex‐detected anti‐HLA Abs in those with graft HLA‐G expression, which reflects a potential protective role of HLA‐G against humoral immunity in LTx. This observation can be related to previous findings in heart Tx patients showing an association of sHLA‐G expression and C4d staining associated with antibody‐mediated rejection . It also agrees with the inhibitory role of HLA‐G in proliferation, differentiation and antibody secretion of B cells recently reported .…”

Section: Discussionsupporting

confidence: 92%

Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study

Brugière

Thabut

Krawice-Radanne

et al. 2015

American Journal of Transplantation

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Human leukocyte antigen G (HLA‐G) expression is thought to be associated with a tolerance state following solid organ transplantation. In a lung transplant (LTx) recipient cohort, we assessed (1) the role of HLA‐G expression as a predictor of graft acceptance, and (2) the relationship between (i) graft and peripheral HLA‐G expression, (ii) HLA‐G expression and humoral immunity and (iii) HLA‐G expression and lung microenvironment. We prospectively enrolled 63 LTx recipients (median follow‐up 3.26 years [min: 0.44–max: 5.03]). At 3 and 12 months post‐LTx, we analyzed graft HLA‐G expression by immunohistochemistry, plasma soluble HLA‐G (sHLA‐G) level by enzyme–linked immunosorbent assay, bronchoalveolar lavage fluid (BALF) levels of cytokines involved in chronic lung allograft dysfunction (CLAD) and anti‐HLA antibodies (Abs) in serum. In a time‐dependent Cox model, lung HLA‐G expression had a protective effect on CLAD occurrence (hazard ratio: 0.13 [0.03–0.58]; p = 0.008). The same results were found when computing 3‐month and 1‐year conditional freedom from CLAD (p = 0.03 and 0.04, respectively [log‐rank test]). Presence of anti‐HLA Abs was inversely associated with graft HLA‐G expression (p = 0.02). Increased BALF level of transforming growth factor‐β was associated with high plasma sHLA‐G level (p = 0.02). In conclusion, early graft HLA‐G expression in LTx recipients with a stable condition was associated with graft acceptance in the long term.

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Section: Discussionsupporting

confidence: 92%

Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study

Brugière

Thabut

Krawice-Radanne

et al. 2015

American Journal of Transplantation

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“…Such an HLA-G inhibitory role on B cell response is in accordance with clinical observations showing reduced HLA alloantibody levels in kidney transplant patients (40) or inhibition of the humoral response in heart transplant patients who express HLA-G (41).…”

Section: Discussionsupporting

confidence: 72%

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

Naji

Menier

Morandi

et al. 2014

The Journal of Immunology

144

126

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Inhibition of B cells constitutes a rational approach for treating B cell–mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2–HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell–dependent and –independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2–HLA-G interaction showed a G0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3β, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2–HLA-G interaction brings important insight to design future B cell–targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases.

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“…Considerable variation was observed in sHLA-G levels (TOL: 63.3±93.5, PW: 92.3±102.4, MI: 67.1± 96.0 ng/ml), and no significant differences were detected between the groups. Recently, it has been reported that in heart transplantation, only 13% of patients with sHLA-G levels >100 ng/ml suffered clinically significant acute cellular rejection compared with 63% of patients with sHLA-G <100 ng/ml (34). Interestingly, in our study population, a higher percentage of patients with sHLA-G levels >100 ng/ml was observed in the TOL group (9 out of 26: 34.6%) compared with PW patients (8 out of 28: 28.5%) and MI patients (6 out of 24: 25.0%) but these differences did not achieve statistical significance.…”

Section: Resultsmentioning

confidence: 99%

HLA-G Level on Monocytoid Dendritic Cells Correlates With Regulatory T-Cell Foxp3 Expression in Liver Transplant Tolerance

et al. 2011

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Background Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule expressed as membrane-bound and soluble isoforms. Interaction of HLA-G with its receptor, immunoglobulin (Ig)-like transcript (ILT) 4 on dendritic cells (DC) down-regulates their T cell stimulatory ability. Methods We examined expression of HLA-G, ILT4, other immune regulatory molecules (inducible costimulator ligand and glucocorticoid-induced tumor necrosis factor-related receptor ligand), and the activation marker CMRF44 on circulating monocytoid (m) and plasmacytoid (p)DC by monoclonal antibody staining and flow cytometry. Three groups of stable liver transplant recipients,-operationally tolerant (TOL), prospective immunosuppressive drug weaning (PW) and maintenance immunosuppression (MI) were studied, together with healthy controls (HC). Serum HLA-G levels were measured by enzyme-linked immunosorbent assay. Results In TOL patients, mDC but not pDC expressed higher HLA-G than in MI patients or HC. In TOL patients, the incidence of CD4+CD25hiCD127− 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 >100ng/ml was highest in the TOL group, although statistical significance was not achieved. Conclusions 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.

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Association Between HLA-G Expression and C4d Staining in Cardiac Transplantation

Cited by 12 publications

References 6 publications

Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study

Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study

Binding of HLA-G to ITIM-Bearing Ig-like Transcript 2 Receptor Suppresses B Cell Responses

HLA-G Level on Monocytoid Dendritic Cells Correlates With Regulatory T-Cell Foxp3 Expression in Liver Transplant Tolerance

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