The association between the risk of allograft rejection after organ transplantation and FAS gene polymorphism has been evaluated previously. However, inconsistent results have been reported. Hence, we conducted the most up-to-date meta-analysis to evaluate this association. All eligible studies reporting the association between FAS-670A＞G polymorphism and the risk of allograft rejection published up to December 2019 were extracted using a comprehensive systematic database search in the Web of Science, Scopus, and PubMed. The pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated to determine the association strength. This meta-analysis included six case-control studies with 277 patients who experienced allograft rejection and 1,001 patients who did not experience allograft rejection (controls) after organ transplantation. The overall results showed no significant association between FAS-670A＞G polymorphism and the risk of allograft rejection in five genetic models (dominant model: OR=0.81, 95% CI=0.58‒1.12; recessive model: OR=0.10, 95% CI=0.80‒1.53; allelic model: OR=0.96, 95% CI=0.79‒1.18; GG vs. AA: OR=0.92, 95% CI=0.62‒1.36; and AG vs. AA: OR=0.75, 95% CI=0.52‒1.08). Moreover, subgroup analysis according to ethnicity and age did not reveal statistically significant results. Our findings suggest that FAS-670A＞G polymorphism is not associated with the risk of allograft rejection after organ transplantation.

An essential milestone in pediatric transplantation is to find noninvasive biomarkers to monitor acute rejection (AR). In this retrospective (Case-control) study, we examined the role of Fas -670A/G and Fas Ligand (FasL) -843C/T gene polymorphisms in allograft nephropathy in pediatric renal transplant recipients.

In 47 pediatric kidney transplant recipients and 20 healthy controls, Fas -670A/G and FasL -843C/T gene polymorphisms as well as serum soluble Fas Ligand level (sFasL) were measured.

Serum sFasL levels were significantly higher in transplant recipients children than that in controls (548.25±298.64pg/ml vs 143.17±44.55pg/ml, p=0.0001). There was no significant difference between patients with AR and those without AR in regards to serum sFasL levels (567.70±279.87pg/ml vs 507.85±342.80pg/ml, p=0.56). Fas -670A/G genotypes or alleles were not significantly different between controls and transplant recipients and among transplant recipients with and without AR. (P>0.05 for all). FasL -843C/T genotypes were not different between transplant recipients and controls and among transplant recipients with and without AR (P>0.05 for all). However, Frequency of C allele in transplant patients was significantly higher than that in the control group (44.68% vs 25%, P=0.03). FasL -843C/T alleles were significantly different between patients with and without AR (P=0.03). The percentages of C allele were higher in children with AR (58.82% vs 36.67%). We found that serum FasL and serum creatinine were variables that were independently associated with AR.

This study suggests that FasL gene polymorphisms in peripheral blood might be accurate in detecting cellular AR.

The FAS and FAS-Ligand (FASL) system is an important apoptosis pathway in the liver. The FAS-mediated pathway functions by binding the FASL on the activated cytotoxic T lymphocytes and Natural Killer (NK) cells to the FAS receptor on infected hepatocytes. FAS and FASL polymorphisms, which are related to apoptosis, might influence the outcome of Hepatitis B Virus (HBV) infection.

Thus, the present study aimed to determine if FAS and FASL promoter polymorphisms are associated with the clinical outcome of HBV infection.

DNA samples were obtained from the infected individuals including chronic carrier (n = 50), chronic hepatitis (n = 50), cirrhosis (n = 25), naturally recovered (n = 26) and compared with those of their matched healthy controls (n = 100). Genotyping for polymorphisms of FAS-670 A/G and -1377 G/A, and FASL -844 C/T was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays.

Multiple analyses for genetic association of FAS and FASL polymorphisms were not statistically different between HBV patients (n = 125) and healthy controls (n = 100). However, genotype and allele frequencies of FASL-844 C/T were significantly different between recovered individuals and patients with cirrhosis (P = 0.02 and P=0.01, respectively). Whereas, FAS-670A/G and -1377G/A polymorphisms were similarly distributed in these two groups (P = 0.8 and P = 0.47, respectively).

The current study results showed that bearing -844T allele in FASL promoter region has a protective effect on cirrhosis and is involved in recovery from infection. In conclusion, it is proposed that HBV infection outcome might be influenced by FASL-844C/T polymorphism through alteration in apoptosis of hepatocytes.

Recently, several important polymorphisms have been identified in T-cell activation and effector pathway genes and have been reported to be associated with inter-patient variability in alloimmune responses. The present study was designed to assess the impact of these genetic variations on the outcomes of allogeneic hematopoietic stem cell transplantation.

We first investigated ten single nucleotide polymorphisms in six genes, CD28, inducible co-stimulator, cytotoxic T-lymphocyte antigen 4, granzyme B, Fas and Fas ligand, in 138 pairs of patients and their unrelated donors and a second cohort of 102 pairs of patients and their HLA-identical sibling donors.

We observed that patients receiving stem cells from a donor with the cytotoxic T-lymphocyte antigen 4 gene CT60 variant allele (AA genotype) had a reduced incidence of grades II-IV acute graft-versus-host disease; however, they experienced early cytomegalovirus infection and relapsed more frequently, which suggested an interaction between the donor cytotoxic T-lymphocyte antigen 4 gene CT60 AA genotype and reduced T-cell alloreactivity. Furthermore, an unrelated donor with the granzyme B +55 variant genotype (AA) was an independent risk factor for development of grades II-IV acute graft-versus-host disease (P=0.024, RR=1.811). Among patients with acute myelogenous leukemia, those with the Fas -670 TT genotype were at higher risk of relapse (P=0.003, RR=3.823). The presence of these susceptible alleles in the donor and/or patient resulted in worse overall survival (54.9% versus 69.5%, P=0.029).

Our data suggest that genotype analysis of T-cell activation and effector pathway genes can be used for risk assessment for patients with hematologic malignancies before hematopoietic stem cell transplantation.

Co-stimulatory factors such as CD86 and apoptotic molecules such as CD95 and CD95L required to start and to turn off the allogenic immune response may also be present as soluble proteins. To determine the role of the soluble forms of CD86 (sCD86), CD95 (sCD95) and CD95L (sCD95L) in the outcome of liver transplants, we analyzed the circulating levels of these molecules in patients subjected to liver transplantation in the pre-operative period and during the first month post-transplantation. Serum samples were obtained from sixty-nine first orthotopic liver transplants (OLT). The patients were classified into acute rejection (AR=24) and not acute rejection (NAR=45), or considering the presence of chronic active hepatitis B or C (VP=30) or other primary liver diseases (VN=39). The levels of sCD86, sCD95 and sCD95L were analyzed by solid phase sandwich enzyme-linked immunoabsorbent assays. Our results first showed that the pre-transplantation serum levels of sCD86 in the AR group were significantly higher than in the NAR group (1007±82U/mL vs. 739±46U/mL, p=0.006), and in the post-transplantation period these levels decreased sharply. Second, the levels of sCD95L and sCD95 in the pre-transplantation period did not point to statistically significant differences between the AR and NAR groups. Considering primary liver disease, the pre-transplantation levels of sCD86 and sCD95L in the VP group were significantly higher than those of the VN group (VP, 977±69U/mL vs. VN, 722±51U/mL, p<0.002, and VP, 482±78pg/mL vs. VN, 221±31pg/mL, p=0.002, respectively). Multivariate analysis revealed that only the pre-transplantation levels of sCD86 were independently associated with the development of episodes of acute rejection (p=0.005, OR=2.1, IC 95%=1.27-3.47). In conclusion, the present work shows that primary liver disease could influence the pre-transplantation levels of sCD86 and sCD95L. High pre-transplantation serum levels of sCD86 could favor the development of episodes of acute rejection.

The aim of the present study was to quantitatively monitor the response of CD95 molecules expressed on CD3(+) T cells (CD95(+)CD3(+) cells) and CD38 molecules expressed on CD8(+) T cells (CD38(+)CD8(+) cells) to ganciclovir treatment after orthotopic liver transplant (OLT) in recipients with active human cytomegalovirus (HCMV) infection.

Blood samples were collected from 20 liver transplanted recipients with active HCMV infection and 24 recipients without HCMV infection. CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were quantitatively detected with QuantiBRITE bead methods by dual-color flow cytometry analysis during the post-transplantation period.

CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were not significantly different among different ages of healthy adults (P > 0.05). CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were drastically increased in the active HCMV infection group compared with that in the stable group or in the healthy group (P < 0.001), and then they were gradually decreased within the next several weeks after ganciclovir treatment when compared with active HCMV infection recipients (P < 0.001).

The present study showed that CD38(+)CD8(+) T cells can be an appropriate immunological marker for early detection and antiviral therapeutic monitoring of HCMV infection. The evaluation of CD95 molecule levels may be used routinely in clinical practice to assess the level of immunosuppression.

Acute rejection (AR) contributes to the development of chronic allograft nephropathy that is the major cause of graft failure. We analyzed the 59029G>A polymorphism and an internal 32 bp deletion (CCR5 32) of CCR chemokine receptor 5 (CCR5) Delta and tried to prove the hypothesis that genetic interactions between the donor and the recipient influence the development of AR.

We detected genetic polymorphisms by the TaqMan(R) method and by sizing PCR amplicons (n = 486). The primary outcomes were early acute rejection (EAR) and repeated early acute rejection (RR). We defined EAR as the occurrence of a biopsy-proven AR within 3 months after transplantation.

The development of EAR was dependent on the number of A alleles in recipients and showed a dose-response relationship (P = 0.002). When we combined the number of A alleles in both donor and recipient, episodes of EAR and RR were more prevalent as the allelic number increased (A allelic number 0 & 1, 2 versus 3 & 4, P = 0.048; 0 & 1 versus 3 & 4, P = 0.006). Statistical significance was preserved after multivariate analysis of sex, HLA mismatch and type of donor with the recipient's age as the continuous term. Also, graft survival was different according to the presence of the A allele, i.e. recipients carrying A allele (+) grafts showed poor graft survival (P = 0.008 by a log-rank test). Again, the number of A alleles affected graft survival as the recipients who carried more A alleles had poor graft survival (A allele number 0 & 1 versus 2 versus 3 & 4, P = 0.011; 0 & 1 versus 3 & 4, P = 0.08; 0 & 1 versus 2, P = 0.002; by a log-rank test). All of the participants were wild-type homozygotes for CCR5Delta32.

The A allele of CCR5 59029G>A was a risk factor for EAR and RR. As the number of A alleles increased, episodes of EAR were more frequently observed.

Despite their efficacy, the calcineurin inhibitors (CNIs) ciclosporin and tacrolimus carry a risk of debilitating adverse effects, especially nephrotoxicity, that affect the long-term outcome and survival of children who are given organ transplants. Simple reduction in dosage of CNI has little or no long-term benefit on their adverse effects, and complete withdrawal without threatening graft outcome may only be possible after liver transplantation. Until the last decade, the only option was to increase corticosteroid and/or azathioprine doses, which imposed additional long-term hazards. Considered here are the emerging generation of new agents offering an opportunity for improving long-term graft survival, minimizing CNI-related adverse events and ensuring patient well-being.A holistic, multifaceted strategy may need to be considered - initial selection and optimized use and monitoring of immunosuppressant regimens, early recognition of indicators of patient and graft dysfunction, and, where applicable, early introduction of CNI-sparing regimens facilitating CNI withdrawal. The evidence reviewed here supports these approaches but remains far from definitive in paediatric solid organ transplantation. Because de novo immunosuppression uses CNI in more than 93% of patients, reduction of CNI-related adverse effects has focused on CNI sparing or withdrawal.A recurring theme where sirolimus and mycophenolate mofetil have been used for this purpose is the importance of their early introduction to limit CNI damage and provide long-term benefit: for example, long-term renal function critically reflects that at 1 year post-transplant. While mycophenolic acid shows advantages over sirolimus in preserving renal function because the latter is associated with proteinuria, sirolimus appears the more potent immunosuppressant but also impairs early wound healing. The use of CNI-free immunosuppressant regimens with depleting or non-depleting antibodies plus sirolimus and mycophenolic acid needs much wider investigation to achieve acceptable rejection rates and conserve renal function. The adverse effects of the alternative immunosuppressants, particularly the dyslipidaemia associated with sirolimus, needs to be minimized to avoid replacing one set of adverse effects (from CNIs) with another. While we can only conjecture that judicious combinations with the second generation of novel immunosuppressants currently in development will provide these solutions, a rationale of low-dose therapy with multiple immunosuppressants acting by complementary mechanisms seems to hold the promise for efficacy with minimal toxicity until the vision of tolerance achieves reality.

Major histocompatibility complex class I-related chain A (MICA) is located at 46 kb centromeric of HLA-B. It is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tgammadelta and T CD8 lymphocytes. Data on MICA polymorphism in different populations are still limited. Our aim was to establish allelic diversity of MICA gene and linkage disequilibrium with HLA-B in our population. DNA was obtained from 154 unrelated healthy individuals from the Murcia region in southeastern Spain. HLA-B genotyping was performed using polymerase chain reaction (PCR)-sequence-specific oligonucleotide probes and allele-specific PCR-sequence-specific primers, and MICA genotyping by using PCR-sequence-specific oligonucleotide probes. A total of 19 MICA alleles were detected on this study. MICA*008 was the most frequent allele (25.3%), followed by MICA*002 (16.1%), MICA*004 (14.9%), MICA*001 (7.8%), MICA*009 and MICA*016 (7.1%), and MICA*010 (4.6%). Eleven alleles had frequencies of <1%. In the haplotype analysis, MICA*008-B*0702 was found to be the most common, followed by MICA*004-B*4403 and MICA*001-B*1801, MICA*002-B*3501, MICA*008-B*4402, MICA*004-B*4901, MICA*008-B*0801, and MICA*002-B*3801. The frequency of MICA*010-B*1501, MICA*008-B*1302, MICA*015-B*4501, and MICA*008-B*4001 was remarkable inasmuch as these two last haplotypes have not been reported in Spanish population. Indeed, MICA*016 linked to B*1402 has also not been reported in the literature. In conclusion, the allelic diversity in our population is similar to other Caucasian populations; however we found a series of less frequent alleles, in addition to as-yet-undescribed haplotypic associations in other populations of Caucasian origin.

Cytokines are known to be important mediators during liver graft outcome and their gene polymorphism could affect the overall expression and secretion of cytokines. In this retrospective study, we analyzed the effect of TGF-beta1 polymorphism in 150 liver allograft recipients. Genotyping PCR-SSP were performed for TGF-beta1 gene (codon 10T/C and 25C/G). TGF-beta1 polymorphism at codon 10 and 25 correlate borderline with liver graft acceptance and when the combination between codon 10 and 25 was analyzed, it revealed that T/T G/C genotype and the TC haplotype were significantly associated with graft acceptance (p<0.05). TGF-beta1 high secretor phenotype was also increased in the acute rejection group close to significance (p=0.06). In conclusion, these findings show a correlation between TGF-beta1 gene polymorphism and liver graft acceptance.

The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network.