Mazariegos, G. | bioRxiv Science

bioRxiv2022

Enhanced donor antigen presentation by B-cells predicts acute cellular rejection and late outcomes after transplantation.

PurposeEnhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT, IT) recipients. MethodsTo test clinical performance, we measured the API using the previously described 6-hour assay in 84 LT and 54 IT with median age 3.3 years (0.05-23.96). Recipients experiencing ACR within 60 days after testing were termed rejectors. ResultsWe first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 days before diagnosis. The API was higher among rejectors compared with non-rejectors (2.2 {+/-} 0.2 vs 0.6 {+/-} 0.04, p-value=1.7E-09). In logistic regression and ROC analysis, API [≥] 1.1 achieved sensitivity, specificity, positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80-88% in 32 independent post-transplant samples, and 73-100% in 20 independent pre-transplant samples. In time-to-event analysis, API [≥] 1,1 predicted higher incidence of late DSA after API measurements in LT (p=0.011) and graft loss in IT recipients (p=0.008), compared with recipients with API<1.1, respectively. ConclusionEnhanced donor antigen presentation by circulating B-cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation

immunology↗

bioRxiv2021

Impaired T-cell and antibody immunity after COVID-19 infection in chronically immunosuppressed transplant recipients

Assessment of T-cell immunity to the COVID-19 coronavirus requires reliable assays and is of great interest, given the uncertain longevity of the antibody response. Some recent reports have used immunodominant spike (S) antigenic peptides and anti-CD28 co-stimulation in varying combinations to assess T-cell immunity to SARS-CoV-2. These assays may cause T-cell hyperstimulation and could overestimate antiviral immunity in chronically immunosuppressed transplant recipients, who are predisposed to infections and vaccination failures. Here, we evaluate CD154-expressing T-cells induced by unselected S antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. Subjects included 72 transplanted and 130 non-transplanted subjects. S-reactive CD154+T-cells co-express and can thus substitute for IFN{gamma} (n=3). Assay reproducibility in a variety of conditions was acceptable with coefficient of variation of 2-10.6%. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed transplant recipients who were sampled pre-pandemic, compared with 59 healthy non-transplanted subjects (p=0.02), b) lower in Tr COVID-19 patients compared with healthy transplant patients (p<0.0001), c) lower in Tr patients with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr recipients. S-reactive T-cells were not significantly different between the various COVID-19 disease categories in NT recipients. Among transplant recipients with COVID-19, cytomegalovirus co-infection occurred in 34%; further, CMV-specific T-cells (p<0.001) and incidence of anti-receptor-binding-domain IgG (p=0.011) were lower compared with non-transplanted COVID-19 patients. Healthy unexposed transplant recipients exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 infection leads to impaired T-cell and antibody responses to SARS-CoV-2 and increased risk of CMV co-infection in transplant recipients.

immunology↗