Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients.

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Genome-wide association study biomarkers in T-cell mediated rejection: selective effect according to the Banff classification.

BACKGROUND: A genome-wide association study (GWAS) in kidney transplant recipients reported the association of two polymorphisms located in the PTPRO gene and upstream of the CCDC67 (DEUP1) gene with increased risk of acute T cell-mediated rejection (TCMR). We aimed at replicating the assessment of mentioned associations and additionally ascertaining the influence of treatment and clinical features of the patients. METHODS: The polymorphisms, PTPRO-rs7976329 and CCDC67-rs10765602 were genotyped by TaqMan chemistry in 641 consecutive kidney transplant recipients. The diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. Associations were evaluated by Chi-square test or Fisher's exact test when necessary and multivariate logistic regression. RESULTS: Considering the GWAS study we only replicated the association of the PTPRO-rs7976329*C allele in the Banff grade < II subjects. However, the homozygous mutant genotypes of both polymorphism seemed to increase the risk of TCMR Banff grade < II in the overall cohort and after stratification by Thymoglobulin induction therapy. In the multivariate analysis, we confirmed the association of PTPRO-rs7976329 with TCMR Banff grade < II, independently of the Thymoglobulin induction therapy and of CCDC67-rs10765602 only in the group of patients not receiving Thymoglobulin induction therapy. No association of these polymorphisms with TCMR Banff grade ≥ II was observed in either the overall cohort or in the subgroups stratified by Thymoglobulin therapy. CONCLUSIONS: Our study shows that the increased risk of TCMR related to polymorphisms PTPRO-rs7976329 and CCDC67-rs10765602 previously reported in a GWAS was replicated only in homozygous patients who presented TCMR Banff grade < II and for the minor allele of either polymorphism.

Hemophagocytic syndrome triggered by donor-transmitted toxoplasmosis as a complication in same-donor recipients of renal transplantation: Case report and review of the literature.

BACKGROUND: Hemophagocytic syndrome (HPS) is an infrequent complication of transplantation caused by an inflammatory response with a benign proliferation of macrophages and defective lytic capability of T lymphocytes and NK cells that can lead to multiorgan failure. Transplant patients are particularly exposed as a result of the increased risk of both infections and malignancies derived from immunosuppressive drugs. There is no consensus for therapy or immunosuppression; mortality is high. We report a case and present a review of all cases of HPS occurring in solid organ transplant recipients.  CASE REPORT: We report two cases of infection by Toxoplasma gondii transmitted by the kidney allograft. One of the recipients was seronegative before transplantation and developed disseminated primary toxoplasmosis. An immune reaction compatible with an HPS ensued. Both were treated with Trimethoprim/sulfamethoxazole, immunosuppression was tapered, and after a 2-week period a complete response was obtained. CONCLUSION: HPS presents therapeutic challenges in the context of transplantation. If HPS is suspected, the search of a very likely underlying infection should be central to the management.

Association of Polymorphisms in T-Cell Activation Costimulatory/Inhibitory Signal Genes With Allograft Kidney Rejection Risk.

The genes CD28, CD86 and CTLA-4 conform the costimulatory (CD28-CD86) or inhibitory (CTLA-4-CD86) signal in T-cell activation. T-cell immune response has a critical role in allograft rejection, and single nucleotide polymorphisms (SNPs) located in these genes have been widely analyzed with controversial results. We analyzed a group of SNPs located in the three genes: CD28: rs3116496; CD86: rs1129055; and CTLA-4: rs231775 and rs3087243 in a cohort of 632 consecutively recruited kidney transplanted subjects. All polymorphisms were genotyped by TaqMan chemistry and the diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. The analyses showed a statistically significant protective effect to T cell-mediated rejection (TCMR) in carriers of the CTLA-4 rs3087243*G allele, especially in patients with TCMR Banff ≥2 in the overall cohort and in patients without thymoglobulin induction therapy. Both associations were corroborated as independent factors in the multivariate analysis. Interestingly, associations with rejection were not found for any SNP in patients with thymoglobulin induction therapy. As expected, considering the major role of these genes in T-cell activation, no effect was observed for antibody-mediated rejection (ABMR). In conclusion, the SNP rs3087243 located in the CTLA-4 gene may be considered a useful independent biomarker for TCMR risk especially for severe TCMR in patients who did no received thymoglobulin induction therapy.

Impacts of Interleukin-18 Polymorphisms on the Incidence of Delayed-Onset Cytomegalovirus Infection in a Cohort of Kidney Transplant Recipients.

BACKGROUND: The incidence of cytomegalovirus (CMV) infection in solid organ transplant recipients may be reduced by antiviral prophylaxis, but this strategy may lead to delayed-onset CMV infection. The proinflammatory cytokine interleukin (IL)-18 plays a major role in viral host defense responses. This study examines the impacts of 2 single-nucleotide polymorphisms (SNPs) in the promoter region of the IL-18 gene, -607C/A (rs1946518) and -137G/C (rs187238), on the incidence of delayed-onset CMV infection in patients undergoing kidney transplant. METHODS: This retrospective study analyzed 2 IL-18 SNPs in consecutive adult kidney transplant recipients using real-time polymerase chain reaction with TaqMan probes. Participants were enrolled over the period 2005-2013 and stratified according to their IL-18 SNP genotype. The concordance index (Harrell's c-index) was used as a measure of the discriminatory power of the predictive models constructed with bootstrapping to correct for optimistic bias. RESULTS: Seven hundred nine patients received transplants in the study period, and 498 met selection criteria. Cytomegalovirus infection and disease incidence were 38% and 7.5%, respectively. In multivariate competing risk regression models, carriers of the -607C/-137G haplotype who received prophylaxis showed a higher incidence of CMV replication after antiviral agent discontinuation (hazard ratio = 2.42 [95% confidence interval, 1.11-5.26]; P = .026), whereas CMV disease was not observed in those given prophylaxis who were noncarriers of this polymorphism (P = .009). CONCLUSIONS: Our findings suggest that the -607C/-137G IL-18 haplotype is associated with a higher incidence of postprophylaxis CMV replication. The prior identification of this polymorphism could help select alternative measures to prevent delayed-onset CMV infection in these patients.