Antibody‐mediated rejection is responsible for 30%‐50% of renal graft failures. Differentiation of B cells into antibody‐producing plasmablasts depends on the collaboration of follicular helper T ...cells (Tfh). We analyzed circulating Tfh (cTfh) in kidney recipients and studied cTfh relationship with anti‐HLA antibody production and graft outcome. cTfh were longitudinally analyzed in a prospective cohort of patients (n = 206), pre‐ and posttransplantation. Clinical data, HLA sensitization, and cTfh function were recorded. Both pretransplant and 6‐month posttransplant cTfh were able to derive IgG‐producing plasmablasts. Pretransplant cTfh was decreased in patients, especially in those who received dialysis. However, these cells were increased in patients with previous allograft or transfusions and in HLA‐sensitized recipients. After transplantation cTfh expanded, significantly more in patients who developed de novo anti‐HLA antibodies than in patients who remained unsensitized. Augmented pretransplant cTfh positively correlated with higher intensity of pretransplant anti‐HLA class I and with de novo anti‐HLA class I and anti‐HLA class II antibodies. Consistently, pretransplantation cTfh were higher in patients who experienced acute rejection (HR = 1.14 1.04‐1.25). Thus, we show a role for Tfh in anti‐HLA sensitization and rejection. Multicenter studies with additional patient cohorts are needed to validate these results. Immunosuppressive drugs targeting Tfh could be useful to improve outcomes.
Circulating follicular helper T cells are associated with anti‐HLA antibody development and acute rejection in renal transplant patients, which points these cells out as a therapeutic target to improve transplant outcome.
Whether immunosuppression impairs severe acute respiratory syndrome coronavirus 2‐specific T cell–mediated immunity (SARS‐CoV‐2‐CMI) after liver transplantation (LT) remains unknown. We included 31 ...LT recipients in whom SARS‐CoV‐2‐CMI was assessed by intracellular cytokine staining (ICS) and interferon (IFN)‐γ FluoroSpot assay after a median of 103 days from COVID‐19 diagnosis. Serum SARS‐CoV‐2 IgG antibodies were measured by ELISA. A control group of nontransplant immunocompetent patients were matched (1:1 ratio) by age and time from diagnosis. Post‐transplant SARS‐CoV‐2‐CMI was detected by ICS in 90.3% (28/31) of recipients, with higher proportions for IFN‐γ‐producing CD4+ than CD8+ responses (93.5% versus 83.9%). Positive spike‐specific and nucleoprotein‐specific responses were found by FluoroSpot in 86.7% (26/30) of recipients each, whereas membrane protein‐specific response was present in 83.3% (25/30). An inverse correlation was observed between the number of spike‐specific IFN‐γ‐producing SFUs and time from diagnosis (Spearman's rho: −0.418; p value = .024). Two recipients (6.5%) failed to mount either T cell–mediated or IgG responses. There were no significant differences between LT recipients and nontransplant patients in the magnitude of responses by FluoroSpot to any of the antigens. Most LT recipients mount detectable—but declining over time—SARS‐CoV‐2‐CMI after a median of 3 months from COVID‐19, with no meaningful differences with immunocompetent patients.
This single‐center study shows that, after a median of 103 days from diagnosis, the majority of liver transplant recipients recovered from COVID‐19 exhibit SARS‐CoV‐2‐specific cell‐mediated immunity detectable by two different methods that was comparable to nonimmunocompromised control patients.
Rejection is one of the most important drawbacks for graft and patient survival in intestinal and multivisceral transplantation. However, there is no consensus on the diagnostic criteria for humoral ...rejection, and the literature about the role of donor‐specific antibodies (DSA) on allograft outcome and the risk factors that contribute to their development is scant with contradictory results. The present study analyzes the role of DSA exclusively in a pediatric cohort of 43 transplants. Among our patients, 11.6% showed preformed DSA, but they did not correlate with more rejection or less allograft survival. Having previous transplants was the main sensitization factor with an odds ratio (OR) = 44.85 (P = 0.001). In total, 16.3% of recipients developed de novo donor‐specific antibodies (dnDSA), mostly directed against human leukocyte antigen (HLA) class II, polyspecific and complement fixing. Additionally, the presence of dnDSA had a deleterious effect on graft rejection (hazard ratio HR = 11.00; P = 0.01) and survival (HR = 66.52; P < 0.001) in an observational period of 5 years after transplantation. The inclusion of the liver emerged as the main protective factor against dnDSA development with an OR = 0.07 (P = 0.007). The analysis of HLA compatibility at the serological and epitope level with the computational tools HLAMatchmaker and PIRCHE revealed no association between HLA mismatching and dnDSA. In conclusion, this study performed in pediatric recipients shows the deleterious effect of dnDSA on intestinal transplantation supported by the complement‐fixing activity observed. Additionally, the liver inclusion in the allografts showed to be a protective factor against dnDSA generation.
Primary infection and/or reactivation of cytomegalovirus (CMV) in kidney transplant recipients (KTR) favor rejection and mortality. T follicular helper cells (TFH) could contribute to protection ...against CMV. Circulatory TFH (cTFH) were studied pretransplant and early posttransplant in 90 CMV seropositive KTR not receiving antithymocyte globulin or antiviral prophylaxis, followed‐up for 1 year. Patients who presented CMV infection had significantly lower cTFH and activated cTFH pretransplant and early posttransplant. Pretransplant activated cTFH were also lower within patients who developed CMV disease. Pre‐ and 14 days posttransplant activated cTFH were an independent protective factor for CMV infection (HR 0.41, p = .01; and 0.52, p = .02, respectively). KTR with low cTFH 7 days posttransplant (<11.9%) had lower CMV infection‐free survival than patients with high cTFH (28.2% vs. 67.6%, p = .002). cTFH were associated with CMV‐specific neutralizing antibodies (Nabs). In addition, IL‐21 increased interferon‐γ secretion by CMV‐specific CD8+ T cells in healthy controls. Thus, we show an association between cTFH and lower incidence of CMV infection, probably through their cooperation in CMV‐specific Nab production and IL‐21‐mediated enhancement of CD8+ T cell activity. Moreover, monitoring cTFH pre‐ and early posttransplant could improve CMV risk stratification and help select KTR catalogued at low/intermediate risk who could benefit from prophylaxis.
Circulatory T follicular helper cells may protect against cytomegalovirus reactivation by promoting neutralizing antibody production and fostering effector cellular responses by secreting IL‐21 and also may serve as a biomarker to identify CMV seropositive patients at high risk of cytomegalovirus reactivation.
Summary
Intestinal grafts carry large donor lymphoid load that is replaced by recipient cells. The dynamics of this process may influence the tolerance, rejection or graft‐versus‐host disease. We ...analysed distribution and turnover of T and B (Lin+) lymphocytes, natural killer (NK) and helper innate lymphoid cells (hILC) in intestinal epithelium (IEp) and lamina propia (LP) from a long‐term cohort of eight intestinal recipients and from a single patient monitored deeply during the first 8 months post‐transplant (posTx). Long‐term intestinal grafts showed significantly higher %hILC than native bowels in IEp and LP until 10 years posTx and recovery to normal levels was observed afterwards. We also observed an imbalance between hILC subsets in IEp increase of type 1 (ILC1) and decrease in type 3 (ILC3) innate lymphoid cells that persisted along posTx time even when %hILC was similar to native bowels. Regarding hILC origin, we still detected the presence of donor cells at 13 years posTx. However, this chimerism was significantly lower than in Lin+ and NK populations. According to these findings, observation from the patient monitored in early posTx period showed that recipient hILC repopulate earlier and faster than Lin+ cells, with increase in ILC1 related to rejection and infection episodes.
This study investigates kidney transplant outcomes in highly sensitised patients after implementing a delisting strategy aimed at enabling transplantation despite preformed donor‐specific antibodies ...(preDSA), with the goal of reducing acute antibody‐mediated rejection (aAMR) risk. Fifty‐three sensitised recipients underwent kidney transplant after delisting prohibited HLA antigens, focusing initially in low MFI antibodies (<5000), except for anti‐HLA‐DQ. If insufficient, higher MFI antibodies were permitted, especially for those without an immunogenic eplet pattern assigned. Delisting of Complement‐fixing antibodies (C1q+) was consistently avoided. Comparison cohorts included 53 sensitised recipients without DSA (SwoDSA) and 53 non‐sensitised (NS). The average waiting time prior to delisting was 4.4 ± 1.8 years, with a reduction in cPRA from 99.7 ± 0.5 to 98.1 ± 0.7, followed by transplantation within 7.2 ± 8.0 months (analysed in 34 patients). Rejection rates were similar among preDSA, SwoDSA, and NS groups (16%, 8%, and 11%, respectively; p = 0.46). However, aAMR was higher in the preDSA group (12%, 4%, and 2%, respectively; p = 0.073), only presented in recipients with DSA of MFI >5000. The highest MFI DSA were against HLA‐DP (Median: 10796 MFI), with 50% of preDSA aAMR cases due to anti‐DP antibodies (n = 3). Graft survival rates at 1 and 5 years in preDSA group were 94%, and 67%, comparable to SwoDSA (94%, and 70%; p = 0.69), being significantly higher in the NS group (p = 0.002). The five‐year recipient survival rate was 89%, comparable to SwoDSA and NS groups (p = 0.79). A delisting strategy enables safe kidney transplant in highly sensitised patients with preDSA, with a slight increase in aAMR and comparable graft and patient survivals to non‐DSA cohorts.
Summary
In transplanted intestines, depletion of T cells together with long‐term persistence of ILC is observed, suggesting ILC insensitivity to immunosuppressive drugs. To further analyze helper ILC ...(hILC) apparent resistance to therapy, cytotoxic ILC (NK cells), hILC subsets (ILC1, ILC2, and ILC precursors (ILCP)), and their signature cytokines (IFNγ, IL4 + IL13, and IL22) were analyzed in peripheral blood of kidney and liver transplant recipients. Early after transplantation (posTx), transplanted patients showed significantly lower Lin + and NK cells, whereas total hILC, ILC1, ILC2, and ILCP numbers were similar in patients and controls. Between paired pre‐ and posTx samples, Lin + cell and NK cell counts significantly decreased, whereas all three hILC counts and their cytokine production remained similar. ILC1, ILC2, and ILCP numbers were also similar in patients under thymoglobulin or basiliximab (BAS), patients without induction (only maintenance therapy) and controls. hILC showed lower TMG binding comparing to Lin + cells, reduced expression of CD25 (BAS target), and diminished calcineurin activity with undetectable calcineurin and FKBP12 (tacrolimus target). hILC counts were not related to delayed graft function or biopsy‐proven acute rejection. Thus, hILC remain stable early after transplantation and seem unaffected by immunosuppressors, which may be related to reduced targets expression and low calcineurin activity.
SARS-CoV-2-specific T cell response has been proven essential for viral clearance, COVID-19 outcome and long-term memory. Impaired early T cell-driven immunity leads to a severe form of the disease ...associated with lymphopenia, hyperinflammation and imbalanced humoral response. Analyses of acute SARS-CoV-2 infection have revealed that mild COVID-19 course is characterized by an early induction of specific T cells within the first 7 days of symptoms, coordinately followed by antibody production for an effective control of viral infection. In contrast, patients who do not develop an early specific cellular response and initiate a humoral immune response with subsequent production of high levels of antibodies, develop severe symptoms. Yet, delayed and persistent bystander CD8+ T cell activation has been also reported in hospitalized patients and could be a driver of lung pathology. Literature supports that long-term maintenance of T cell response appears more stable than antibody titters. Up to date, virus-specific T cell memory has been detected 22 months post-symptom onset, with a predominant IL-2 memory response compared to IFN-γ. Furthermore, T cell responses are conserved against the emerging variants of concern (VoCs) while these variants are mostly able to evade humoral responses. This could be partly explained by the high HLA polymorphism whereby the viral epitope repertoire recognized could differ among individuals, greatly decreasing the likelihood of immune escape. Current COVID-19-vaccination has been shown to elicit Th1-driven spike-specific T cell response, as does natural infection, which provides substantial protection against severe COVID-19 and death. In addition, mucosal vaccination has been reported to induce strong adaptive responses both locally and systemically and to protect against VoCs in animal models. The optimization of vaccine formulations by including a variety of viral regions, innovative adjuvants or diverse administration routes could result in a desirable enhanced cellular response and memory, and help to prevent breakthrough infections. In summary, the increasing evidence highlights the relevance of monitoring SARS-CoV-2-specific cellular immune response, and not only antibody levels, as a correlate for protection after infection and/or vaccination. Moreover, it may help to better identify target populations that could benefit most from booster doses and to personalize vaccination strategies.
Abstract
Incomplete non-sterile immunity to malaria is attained in endemic regions after recurrent infections by a large percentage of the adult population, who carry the malaria parasite ...asymptomatically. Although blood-stage
Plasmodium falciparum
rapidly elicits IgG responses, the target antigens of partially protective and non-protective IgG antibodies as well as the basis for the acquisition of these antibodies remain largely unknown. We performed IgG-immunomics to screen for
P. falciparum
antigens and to identify epitopes associated with exposure and clinical disease. Sera from malaria cases identified five prevalent antigens recognized by all analyzed patients’ IgGs. Epitope mapping of them, using adult and children sera samples from an endemic malaria region in Ghana segregated into patients with positive or negative subclinical detection of
P. falciparum
, revealed binding specificity for two 20-mer immunodominant antigenic regions within the START-related lipid transfer protein and the protein disulfide isomerase PDI8. These 20-mer epitopes challenged with sera samples from children under 5 years old displayed specific IgG binding in those with detectable parasitemia, even at subclinical level. These results suggest that humoral response against START and PDI8 antigens may be triggered at submicroscopic parasitemia levels in children and may eventually be used to differentially diagnose subclinical malaria in children.
The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible ...association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up. Four groups were established according to maximum degree of disease progression. T-helper cell percentages and phenotypes, analyzed by flow cytometer, and serum cytokines levels, analyzed by Luminex, were evaluated when the microbiological diagnosis (acute phase) of the disease was obtained. Our study found a significant reduction of %Th1 and %Th17 cells with higher activated %Th2 cells in the COVID-19 patients compared with reference population. A higher percent of senescent Th2 cells was found in the patients who died than in those who survived. Senescent Th2 cell percentage was an independent risk factor for death (OR: 13.88) accompanied by the numbers of total lymphocytes (OR: 0.15) with an AUC of 0.879. COVID-19 patients showed a profile of pro-inflammatory serum cytokines compared to controls, with higher levels of IL-2, IL-6, IL-15, and IP-10. IL-10 and IL-13 were also elevated in patients compared to controls. Patients who did not survive presented significantly higher levels of IL-15 than those who recovered. No significant differences were observed according to disease progression groups. The study has shown that increased levels of IL-15 and a high Th2 response are associated with a fatal outcome of the disease.
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