Immunosuppressed Kidney Transplant Patients Research Articles

Differences in Responses of Immunosuppressed Kidney Transplant Patients to Moderna mRNA-1273 versus Pfizer-BioNTech.

Immunosuppressed kidney transplant (KT) recipients produce a weaker response to COVID-19 vaccination than immunocompetent individuals. We tested antiviral IgG response in 99 KT recipients and 66 healthy volunteers who were vaccinated with mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech vaccines. A subgroup of participants had their peripheral blood leukocytes (PBLs) evaluated for the frequency of T helper 1 (Th1) cells producing IL-2, IFN-γ and/or TNF-α, and IL-10-producing T-regulatory 1 (Tr) cells. Among KT recipients, 45.8% had anti-SARS-CoV-2 IgG compared to 74.1% of healthy volunteers (p = 0.009); also, anti-viral IgG levels were lower in recipients than in volunteers (p = 0.001). In terms of non-responders (≤2000 U/mL IgG), Moderna's group had 10.8% and Pfizer-BioNTech's group had 34.3% of non-responders at 6 months (p = 0.023); similarly, 15.7% and 31.3% were non-responders in Moderna and Pfizer-BioNTech groups at 12 months, respectively (p = 0.067). There were no non-responders among controls. Healthy volunteers had higher Th1 levels than KT recipients, while Moderna produced a higher Th1 response than Pfizer-BioNTech. In contrast, the Pfizer-BioNTech vaccine induced a higher Tr1 response than the Moderna vaccine (p < 0.05); overall, IgG levels correlated with Th1(fTTNF-α)/Tr1(fTIL-10) ratios. We propose that the higher number of non-responders in the Pfizer-BioNTech group than the Moderna group was caused by a more potent activity of regulatory Tr1 cells in KT recipients vaccinated with the Pfizer-BioNTech vaccine.

Immunogenicity of the meningococcal polysaccharide conjugate vaccine in pediatric kidney transplant patients.

Immunosuppressed kidney transplant patients may have suboptimal response to vaccinations. The aim of this study was to determine antibody response to a quadrivalent meningococcal conjugate vaccine (MenACWY-D) in adolescents with a kidney transplant. This was a prospective, single-center, cohort study. Adolescent patients (11-22years old) with a functioning kidney transplant for at least 3months and no previous meningococcal vaccination were eligible for enrollment. Antibody levels to all serogroups were measured before vaccination (baseline) and at 4weeks and 1, 2 and 3years after vaccination. Seropositivity was defined as a titer ≥ 1:8 at baseline, and seroconversion as a fourfold or greater increase in antibody titer from baseline at 4weeks post-vaccination. Geometric mean titers (GMTs) were calculated at each time point and compared to published GMTs from vaccinated healthy adolescents. Nineteen patients were enrolled. No patient had seroprotective titers against all four serogroups at baseline. At 4weeks post-vaccination 41% of patients seroconverted to all four serogroups, with seroconversion rates of 88, 53, 71 and 94% for serogroups A, C, W and Y, respectively. GMTs were significantly lower in adolescents with a kidney transplant than in healthy adolescents at 1month (p = 0.02) and 3years (p = 0.04) post-vaccination. There were no significant adverse events, episodes of rejection or death in any patient. Adolescents with a kidney transplant may not respond adequately to MenACWY-D and may experience more rapid declines in antibody titers than healthy adolescents. Further study is needed to determine if alternative dosing schedules can improve antibody response in this population.

Immunosuppression and the occurrence of HPV in kidney transplant patients verified by urinary cytology

Introduction: Human papillomavirus (HPV) is the main cause of cervical cancer, and immunosuppression is recognized as a risk factor for HPV infection and its persistence. After renal transplantation, immunosuppressive agents are used to prevent rejection, but predispose recipients to chronic infections and malignancies. Objective: This study aimed to verify, based on urinary cytology (UC), the prevalence of HPV in immunosuppressed kidney transplant patients. Material and method: In this cross-sectional study, the population was composed of kidney transplant patients that had undergone routine UC from August 2012 to August 2014. Results: There were 2,305 urine cytopathological tests. Thirteen patients with presence of koilocytes in such examination were observed. Therefore, the relative frequency of patients with HPV detected in urine was 0.56%. In the interval until the first post-transplant year, 10 (76.92%) patients presented koilocytes (p < 0.0001) in the UC. The dosages of immunosuppressive agents until the first post-transplant consultation, which showed correlation with the period between transplantation and the first UC test with the presence of koilocytes (p < 0.0001), were prednisone 10.5-20 mg/day, mycophenolate sodium 901-1,440 mg/day, and tacrolimus 4.5-12 mg/day. Conclusion: This study showed immunosuppression as an important risk factor for infection by HPV or its reactivation. Screening UC tests after transplantation may evidence HPV infection.

A revised strategy for monitoring BKV-specific cellular immunity in kidney transplant patients

Reactivation of Polyomavirus BKV is a severe complication in kidney transplant patients. Current treatment requires close monitoring, and modification of immunosuppressive drugs. As an important additional tool, the monitoring of BKV immunity has been based on detection of cytokine-secreting T cells upon BKV-antigen challenge. However, low frequent BKV-specific T cells are often barely detectable and their roles in BKV clearance remain unclear. Here, we analyzed the effects of immunosuppressive agents on BKV-specific T cells in vitro. Significant reductions in expression of several markers, and reduced killing functions upon treatment with calcineurin but not mTOR inhibitors were detected. However, effects of these drugs on expression of surface markers and GranzymeB were substantially less striking than effects on cytokine expression. Consequently, we applied a novel detection strategy for BKV-specific T cells in immunosuppressed kidney transplant patients using these more robust markers, and showed significantly improved sensitivity compared with the conventional IFNγ-based method. Using this strategy and 17-color flow cytometry, we found BKV-specific helper and cytolytic CD4+ T-cell subsets that differed in their memory phenotype, which corresponded with BKV clearance in kidney transplant patients. Thus, our results offer an improved detection strategy for BKV-specific T cells in kidney transplant patients, and shed light on the contributions of these cells to BKV clearance.

Disseminated adenoviral infection masquerading as lower urinary tract voiding dysfunction in a kidney transplant recipient

Viral infections continue to cause significant morbidity in immunosuppressed kidney transplant patients. Although cytomegalovirus, Epstein-Barr virus and polyoma "BK" virus are more frequently encountered, the Adenovirus can cause multi-organ system infections, and may be difficult to diagnose because it is not often considered in the initial work up in kidney transplant recipients. We present an unusual case of a kidney recipient 1 year post-transplant with disseminated adenoviral infection, who had an initial presentation of lower urinary tract voiding dysfunction with hematuria and sterile pyuria. This progressed to a severe tubulointerstitial nephritis and acute kidney injury that improved with reduction of immunosuppression. Serial blood viral loads are useful for monitoring the course of infection. Urinary adenoviral infection should be considered in the differential diagnosis whenever a kidney transplant recipient presents with unexplained lower tract voiding dysfunction, hematuria, and sterile pyuria. The allograft kidney and bladder can be targets of viral proliferation. Early diagnosis with reduction of immunosuppressive therapy is essential to clear the virus and maintain allograft function.

Poster Board Number: 18: Correlation Between Immunosuppressed Kidney Transplant Patients and the Occurrence of Oral Squamous Cell Carcinoma at Tufts New England Medical Center: A Retrospective Study

Objective: The most effective management of end stage renal failure is renal transplantation. In recent years, the incidence of cancer has increased in renal transplant recipients due to immunosuppressive therapy used to prevent and treat acute transplant rejection. The use of immunosuppressive therapy has made it possible to reduce the incidence of acute rejection, while improving renal graft survival, but at the expense of increased infections and post-transplant neoplasms. The aim of this retrospective study is to review the occurrence and development of oral squamous cell carcinoma (SCC) in kidney transplant patients between 1998 - 2003 at Tufts New England Medical Center and to compare it to the rate of development of SCC in the general population.

A comparative study of Merkel cell, BK and JC polyomavirus infections in renal transplant recipients and healthy subjects

Background Merkel cell carcinoma (MCC) is a rare skin cancer associated with immunosuppression and the integration of Merkel cell polyomavirus (MCPyV) DNA into the tumor cell genome. Little is known about the natural history of MCPyV infection. Objectives To investigate the presence of MCPyV, BK and JC polyomaviruses in serum and urine from immunosuppressed kidney transplant patients (KTx) and a control group of normal volunteers. Study design Quantitative real-time PCR (q-PCR) was used to assess MCPyV, BKV and JCV viral load in urine and serum samples collected from normal donors (Group A), prospectively enrolled KTx patients (Group B) and from KTx with documented BK reactivation and/or nephropathy (Group C). Results Low levels of MCPyV viruria was seen in 15% of the subjects in Group A, 30% of Group B, and was not detected in Group C. No individuals in the study developed MCPyV viremia. BK viruria was seen in 5% of Group A, 30% of Group B, and 100% of Group C. Consistent with previous reports, the mean BKV urinary load was significantly higher in immunosuppressed patients compared to non-immunosuppressed controls and also higher in urine compared to serum samples. Conclusions Like BKV and JCV, MCPyV is likely a common infection in adult humans. Low level shedding of MCPyV in urine was similar in immunosuppressed organ transplant recipients to non-immunosuppressed subjects. However, MCPyV was not detected and JCV was infrequent in samples from KTx patients with clinical BKV reactivation.

Functional analysis of CD4+ CD25bright T cells in kidney transplant patients: improving suppression of donor-directed responses after transplantation

The role of CD4(+) CD25(bright) regulatory T cells (Treg) in controlling alloreactivity is established, but little is known whether antigen-specific Treg are induced in fully immunosuppressed kidney transplant patients. The frequency and function of CD25(bright) T cells of nine stable kidney transplant patients before and 0.5-2 yr after transplantation were measured. Patients received triple therapy consisting of cyclosporine, mycophenolate mofetil and prednisone. To investigate the influence of transplantation and immunosuppression on Treg function, we compared their suppressive capacities pre- and post-transplantation using mixed lymphocyte reactions and kept the CD25(-/dim) effector T-cell (Teff) population constant. After transplantation, the percentage of CD4(+) CD25(bright) T cells significantly decreased from 8.5% pre-transplant to 6.9% post-transplant (median, p = 0.05). However, the lower percentage of post-transplant CD4(+) CD25(bright) T cells was not associated with reduced, but rather improved suppressor function of these cells. The proliferative response of pre-transplant Teff to donor-antigens was more profoundly suppressed by post-transplant Treg than by pre-transplant Treg (pre-transplant 18% vs. post-transplant 55% median, p = 0.03) and was comparable against third party antigens at a CD25(bright):CD25(-/dim) ratio of 1:20. In immunosuppressed kidney transplant patients, the donor-directed suppressive capacity of CD4(+) CD25(bright) regulatory T cells improved, which may contribute to the development of donor-specific hyporesponsiveness against the graft.

Functional CD25bright+ alloresponsive T cells in fully immunosuppressed renal allograft recipients

Evidence from animal studies indicate a crucial role for CD25(bright+) regulatory T cells in transplantation tolerance. To assess whether peripheral CD25(bright+) T cells control immune responses in immunosuppressed kidney transplant patients, we analyzed the suppressive capacities of these cells using mixed lymphocytes reactions. Allogeneic stimulation of patients peripheral blood mononuclear cells was associated with IL-2 production and T-cell proliferation. Depletion of CD25(bright+) T cells resulted in a 35% (median) higher IL-2 production and a 38% higher proliferative response against third party cells, showing that functional regulatory CD25(bright+) T cells were present (p = 0.03 and 0.02 respectively). In eight out of 11 patients, we also demonstrated regulation activity against donor-activated T cells (p = 0.03). These data were confirmed in coculture experiments with isolated CD25(-/dim) T cells plus CD25(bright+) T cells. At a 1:2 ratio, the CD25(bright+) T cells suppressed the proliferation of CD25(-/dim) donor- and third party-stimulated responder T cells. CD25(bright+) T cells with immune regulatory activities against anti-donor-responsive T cells are readily detectable in renal allograft recipients during treatment with full dosage immunosuppression. Whether CD25(bright+) T cells indeed play a role in graft acceptance after organ transplantation in patients remains to be elucidated.

Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients.

The CD26 antigen, one of the major costimulatory molecules in T cell activation, was shown to possess dipeptidyl peptidase IV (DPP IV) activity. Previously, we demonstrated that immunosuppressed kidney transplant patients exhibit lower DPP IV serum activity as compared with healthy individuals. In the present study, we analyzed the role of CD26/DPP IV in the immune cascade triggered by organ transplantation and leading to acute rejection of cardiac allografts in rat recipients. Transplantation of hearts from (Lewis x Brown Norway)F1 donors into Lewis hosts resulted in an early (24 hr) increase in cellular CD26 expression, followed by a rise in DPP IV serum activity, which peaked at day 6, i.e., before the time of actual graft loss. Specific targeting of DPP IV activity with a novel, low-molecular-weight inhibitor of the diphenyl-phosphonate group (prodipine) abrogated acute rejection and prolonged cardiac allograft survival to 14.0+/-0.9 days (P<0.0001). Prodipine treatment prevented the early peak of cellular CD26 expression and thoroughly suppressed systemic DPP IV activity. The inhibition of DPP IV was associated with severely impaired host cytotoxic T lymphocyte responses in vitro. These results demonstrate the role of CD26/DPP IV in alloantigen-mediated immune regulation in vivo and provide the first direct evidence that CD26/DPP IV plays an important role in the mechanism of allograft rejection. The model of targeting CD26/DPP IV may reveal essential interactions on the level of costimulatory alternate T cell activation pathways, allowing a more subtle approach for more selective immunosuppression in transplant recipients.

A novel method for efficient amplification of whole hepatitis B virus genomes permits rapid functional analysis and reveals deletion mutants in immunosuppressed patients

Current knowledge of hepatitis B virus (HBV) sequence heterogeneity is based mainly on sequencing of amplified subgenomic HBV fragments. Here, we describe a method which allows sensitive amplification and simplified functional analysis of full-length HBV genomes with or without prior cloning. By this method, a large number of HBV genomes were cloned from sera of six immunosuppressed kidney transplant patients. Two size classes of HBV genomes, one 3.2 kb and another about 2.0 kb in size, were found in all patients. The genome population from one serum sample was studied in detail by size analysis of subgenomic PCR fragments and sequencing. Regions with deletions and insertions were mapped in the C gene and pre-S region. Up to 100% of HBV genomes in all other immunosuppressed patients also had deletions in the C gene. Our results demonstrate the potential of the established method for the structural and functional characterization of heterogeneous populations of complete virion-encapsidated HBV DNAs and suggest that HBV genomes with C gene deletions can have a selective advantage in immunosuppressed patients.