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Background: After a transplant, cancer is a leading cause of morbidity and mortality. Human leukocyte antigen-G (HLA-G)-an immune checkpoint molecule-reduces allograft rejection by dampening host immune responses. Reports suggest malignant cells utilize HLA-G to evade the immune system and promote cancer development. Our objective was to evaluate HLA-G donor-recipient polymorphism matching and development of cancer after a heart transplant., Methods: Recipients (n = 251) and corresponding donors (n = 196) were genotyped retrospectively to identify HLA-G polymorphisms in the 5' regulatory (-725, -201), 3' untranslated (+3,197, +3,187, +3,142, 14-base pair insertion-deletion polymorphism [14-bp indel]) and coding regions (Haplotypes I-VI). Associations between donor-recipient polymorphism matching and development of cancer were assessed through multivariate proportional hazard regression models., Results: Recipient and donor (48.2 ± 12.1 and 35.5 ± 14.3 years, respectively) mean follow-up was 7.2 ± 4.6 years. Overall, 42 (16.7%) recipients developed de novo post-transplant cancer. 14-bp polymorphism matching significantly reduced the proportion of cancer, revealing an independent protective effect (hazard ratio [95% CI]: 0.26 [0.10-0.75]; p = 0.012). Recipients with the 14-bp insertion sequence, whether homozygous or heterozygous, had a lower proportion of cancer (p > 0.008), matching the INS sequence (INS/INS and INS/DEL) protected against cancer (p = 0.002). No differences were seen between matched vs unmatched cohorts regarding all donor-recipient pre-transplant and post-transplant characteristics. No other polymorphisms showed significant associations., Conclusions: We investigated donor-recipient HLA-G polymorphism matching and development of cancer following a heart transplant. Donor-recipient 14-bp matching was an independent protective factor against cancer development. HLA-G may have a role in therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy to reduce post-transplant cancer risk., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Rejection is a leading cause of mortality following heart transplantation. Human leukocyte antigen-G (HLA-G) is an immune checkpoint which dampens the immune response. Reports suggest elevated HLA-G expression is associated with reduced allograft rejection. Our objective was to evaluate HLA-G polymorphisms and cell mediated rejection (CMR) development., Methods: Recipients (n = 123) were genotyped to identify relevant HLA-G polymorphisms in the 5'regulatory (-725, -201), 3'untranslated (+3197, +3187, +3142, 14-bp indel) and coding regions (haplotypes 1-6). CMR was evaluated via endomyocardial biopsy (grade ≥ 2R). Univariate/adjusted analyses were conducted via Kaplan Meier and proportional hazard models., Results: Mean recipient age was 48 (±12) years, with a median time to CMR of 4.6 years. 55 (45%) recipients had a biopsy grade ≥ 2R. Adjusted analysis revealed the +3196 G allele as a risk factor for CMR (p = 0.03). Compared to the minor GG genotype, CG had a 47.2% reduction in CMR risk (HR[95% CI] = 0.528 [0.235, 1.184]), while CC had a 66.9% reduction (0.331 [0.144, 0.761]). The recessive effect significantly increased CMR likelihood (2.388 [1.128, 5.059], p = 0.02)., Conclusion: The HLA-G +3196 G allele was identified as a risk factor for CMR diagnosis. HLA-G may have a role in therapeutic/diagnostic strategies against transplant rejection., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

The Human Leukocyte Antigen-G (HLA-G) is a MHC-class Ib molecule with robust immunomodulatory properties; in transplant, it inhibits cytotoxic activity of immune cells and thus has a pivotal role in protecting the allograft from immune attack. The present review details a 10-year experience investigating the influence of HLA-G on heart transplantation, allograft rejection and cardiac allograft vasculopathy development. Exploration of HLA-G in transplantation began with the initial findings of its increased expression in allograft hearts. Since then, HLA-G has been recognized as an important factor in transplant immunology. We discuss inducers of HLA-G expression, and the importance of HLA-G as a potential biomarker in allograft rejection and heart failure. We also highlight the importance of polymorphisms and how they may influence both HLA-G expression and clinical outcomes. There remains much to be done in this field, however we hope that findings from our group and other groups will ignite interest and facilitate further expansion of HLA-G research in transplantation., (Copyright © 2018. Published by Elsevier Inc.)

Human Leukocyte Antigen-G (HLA-G) is a non-classical class 1b protein, whose gene is located on chromosome 6 (6p21.31). HLA-G inhibits the immune cells' cytotoxic activity by interacting with specific receptors on their membranes. Since it is a naturally occurring immune modulator, HLA-G has been investigated in transplantation. Indeed, a number of investigations reveal that HLA-G expression is influenced by genetic polymorphisms and in turn, those polymorphisms are associated with detrimental or beneficial outcomes in various pathological situations. The present review introduces the HLA-G molecule, the gene and its polymorphisms. It focuses on the expression of HLA-G and the role of polymorphisms primarily in heart transplant outcomes, secondarily in other transplant organs, as well as the role of the allograft and effect of medical therapy. We discuss the limitations in HLA-G transplant investigations and future directions. The immune inhibiting activity of HLA-G has a great deal of potential for its utilization in enhancing diagnostic, preventive and therapeutic strategies against rejection in the setting of transplantation., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A 14 bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with mRNA stability and HLA-G expression. In cardiac transplantation, the 14 bp deletion polymorphism plays an important role in the expression of HLA-G and is associated with fewer episodes of cellular rejection. We investigated the association between the 14 bp insertion/deletion HLA-G polymorphism and cardiac allograft vasculopathy (CAV) post heart transplantation. There were no statistically significant differences in the presence of the three HLA-G genotypes (-14 bp/-14 bp, +14 bp/-14 bp, +14 bp/+14 bp) between patients without CAV and patients with CAV at 1 year (p=0.61) or 5 years (p=0.76) post-transplant. We found no correlation between HLA-G genotypes and CAV progression from baseline to 5 years post-transplant (p=0.55). HLA-G polymorphism appears to play an important role as a genetic indicator for cellular rejection post-transplant; however, it is not a reliable marker to identify patients at risk of CAV., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Human leukocyte antigen G (HLA-G) is a non-classical Ib molecule in the major histocompatibility complex. HLA-G has important immunosuppressive properties, and in the context of cardiac transplantation, is associated with a low risk of cellular rejection. A 14-bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with messenger RNA (mRNA) stability and expression of HLA-G. This study analyzed the relationship between HLA-G polymorphisms and serum HLA-G levels in patients after cardiac transplantation to determine if any specific HLA-G genotype is associated with cellular rejection., Methods: Ninety-four heart transplant patients were genotyped for the 14-bp polymorphism. Serum HLA-G levels and cellular rejection grades were evaluated in all patients., Results: The 14-bp polymorphism was significantly associated with serum HLA-G expression. Patients with the -14-bp/-14-bp genotype had significantly higher mean serum HLA-G levels (88.2 U/ml) than those patients with the +14-bp/-14-bp (52.8 U/ml) and +14-bp/+14-bp (32.2 U/ml) genotypes (p = 0.004). The -14 bp/-14-bp genotype was significantly associated with fewer episodes of cellular rejection., Conclusions: This study suggests that the 14-bp deletion in the HLA-G gene plays an important role in the expression of HLA-G and thus might be a clinically useful genetic indicator for cellular rejection risk after cardiac transplantation., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Human leukocyte antigen-G (HLA-G), a non-classical MHC I protein with restricted tissue expression, plays an essential role in immune tolerance and has been negatively associated with acute and chronic rejection after heart transplantation. We assessed myocardial HLA-G expression in adult heart transplant patients in an attempt to determine the value of this protein in identifying patients with a low risk of acute cellular rejection., Methods: Two groups of patients were included in this study. Group A (non-rejecting) included 29 patients who had no moderate or severe rejection episodes (ISHLT Grade <2R) post-transplant. Group B (rejecting) included 38 patients with at least two moderate or severe rejection episodes (Grade >or=2R) within a 1-year period. Expression of HLA-G in three myocardial biopsies post-transplant from each patient was determined through immunohistochemical staining., Results: In Group A, 86% of patients had HLA-G(+) biopsies compared with 11% of patients in Group B (p < 0.001; sensitivity 86%, specificity 87%). Whereas 60% of non-rejecting HLA-G(+) patients had at least two positive biopsies, all rejecting HLA-G(+) patients had only one positive biopsy., Conclusions: There is a significant negative association between myocardial HLA-G expression and acute cellular rejection after cardiac transplantation. Detection of HLA-G appears to reliably indicate a low risk of developing moderate or severe allograft rejection and may, subsequently, allow for a reduced immunosuppressive regimen.

Background: Gastrointestinal (GI) intolerance to mycophenolate mofetil (MMF) is a frequent problem. We conducted a retrospective analysis of all the heart transplant patients followed up at the Toronto General Hospital from the years 1999 to 2006 to determine the impact of dose reductions for GI intolerance on rejection rates., Methods: The charts of all patients followed up in the heart transplant clinic at the Toronto General Hospital from the years 1999 to 2006 were reviewed. Sustained significant rejection was defined as an International Society of Heart and Lung Transplantation grade 2 or higher on 2 successive biopsies. The Student's t-test was used to compare rates of rejection between populations., Results: Mycophenolate mofetil was part of the anti-rejection regimen in 182 of 189 patients (98%), and the medication dose in 71% of these patients had to be reduced at some point because of intolerance or toxicity. The prevalence of sustained significant rejection was significantly higher in the group of patients with GI intolerance to MMF compared with patients maintained on target doses (66% vs 35%, p = 0.002) or patients with non-GI related toxicities necessitating dose reduction (67% vs 35%, p = 0.003)., Conclusion: Gastrointestinal intolerance is a common reason for MMF dose reduction in heart transplant patients and was associated with a significantly increased rate of sustained rejection, suggesting that these individuals need to have particularly close follow-up.

Background: The use of basiliximab or rabbit anti-thymocyte globulin (RATG) for induction therapy has significantly reduced the incidence of acute rejection episodes post-transplantation. The purpose of this study was to compare the safety and efficacy of basiliximab vs RATG in a population of adult heart transplant recipients., Methods: We retrospective analyzed the safety and efficacy of basiliximab compared with RATG among 48 adult heart transplant recipients at our center. Twenty-five patients received basiliximab (20 mg on days 0 and 4 after heart transplantation), and 23 patients received RATG (1.5 mg/kg for 3 days). A standard triple-drug immunosuppression regimen was administered to all patients., Results: The average biopsy score (ABS) at 1 month was 0.79 +/- 0.18 in the Basiliximab Group vs 0.47 +/- 0.2 in the RATG group (p = 0.023) and at 3 months was 0.75 +/- 0.24 in the Basiliximab Group vs 0.46 +/- 0.12 in the RATG Group (p = 0.032). At 6 months after transplantation, the difference between groups was not statistically significant (0.97 +/- 0.23 vs 0.58 +/- 0.17, p = .14). At 12 months the ABS was 0.85 +/- 0.4 in the Basiliximab Group vs 0.63 +/- 0.15 in the RATG Group (p = 0.12), and the number of episodes of infection was similar in both groups (19 vs 26; p = 0.16). There was no correlation between cumulative cyclosporine doses and rejection. Creatinine clearance levels were not statistically different between groups at baseline and up to 12 months after heart transplantation. Three patients died in the Basiliximab Group, and 2 patients died in the RATG Group., Conclusions: Rabbit anti-thymocyte globulin is more effective than basiliximab for prevention of rejection episodes after heart transplantation. Both induction agents provide similar safety profile.

Background: Cyclosporine 2-hour post-dose (C2) monitoring is predictive of outcomes in solid-organ transplants. The purpose of this study was to determine C2 levels at various time points after heart transplantation and determine whether trough (C0) or C2 better predicts clinical outcomes., Methods: This was a 2-phase prospective study with paired determinations of cyclosporine levels at C0 and C2 in 58 heart transplant patients (46 men; mean age, 56 years). Phase I (6-month follow-up): cyclosporine monitored according to C0 levels (C2 blinded). Phase II (6-month follow-up): cyclosporine monitored according to C2 levels (C0 blinded). Clinical outcomes assessed were severe infections, rejection score, and renal dysfunction., Results: No differences were observed in renal function between the phases. In Phase I, 8 infections (4 severe) and in Phase II, 6 infections (2 severe) were detected. During Phase I, the C0 levels did not correlate (p = .96) with the presence (195 +/- 121 ng/ml) or not (197 +/- 100 ng/ml) of rejection. During Phase II, C0 levels did not correlate (p = .88) with the presence (204 +/- 85 ng/ml) or not (209 +/- 138 ng/ml) of rejection. During Phase I, C2 levels did correlate (p = 0.022) with the presence (777 +/- 326 ng/ml) or not (1,015 +/- 422 ng/ml) of rejection. During Phase II, higher C2 levels showed a significant correlation (p = 0.03) with no rejection (967 +/- 470 ng/ml vs 765 +/- 297 ng/ml, no rejection vs rejection, respectively)., Conclusion: High C2 levels were associated with less episodes of acute cellular rejection in patients post-heart transplantation. Monitoring with C2 levels is feasible and safe in terms of preservation of renal function and infection rates.

Background: Human leukocyte antigen-G (HLA-G), a protein primarily expressed during pregnancy, helps maintain maternal–fetal immune tolerance. Myocardial and/or soluble HLA-G (sHLA-G) expression confers protection against rejection and vasculopathy after heart transplantation. Although the precise mechanisms remain unclear, immunosuppressive therapy has been reported to influence this expression. Methods: We compared sHLA-G expression in heart transplant recipients receiving two different anti-proliferative agents: mycophenolate mofetil (MMF) and everolimus (RAD). Twelve-hour pharmacokinetic (PK) studies were conducted in patients after cyclosporine (CsA) administration in conjunction with RAD or MMF, during which plasma HLA-G concentrations were measured by enzyme-linked immunoassay (ELISA). Results: Among patients receiving RAD, 78% expressed detectable levels of plasma HLA-G (1,002 ± 511 ng/ml) compared with 25% of patients receiving MMF (612 ± 438 ng/ml, p = 0.03). In all sHLA-G+ patients, expression remained constant, with no significant changes in HLA-G levels throughout the 12-hour PK study period. CsA did not appear to influence sHLA-G expression, as there was no correlation between HLA-G levels and CsA exposure (R 2 = 0.43, p = 0.08). Conclusions: These preliminary findings suggest a disproportionate expression of HLA-G in patients under two distinct immunosuppression strategies after heart transplantation. Although CsA administration does not influence sHLA-G levels, RAD but not MMF is associated with sHLA-G expression. Larger prospective clinical investigations are required to confirm whether RAD is independently associated with increased HLA-G expression. [Copyright &y& Elsevier]