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BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.

We present a systematic review and pooled analysis of clinical studies to date that (1) specifically compare the protection of natural immunity in the COVID-recovered versus the efficacy of complete vaccination in the COVID-naive, and (2) the added benefit of vaccination in the COVID-recovered, for prevention of subsequent SARS-CoV-2 infection. Using the PRISMA 2020 guidance, we first conducted a systematic review of available literature on PubMed, MedRxIV and FDA briefings to identify clinical studies either comparing COVID vaccination to natural immunity or delineating the benefit of vaccination in recovered individuals. After assessing eligibility, studies were qualitatively appraised and formally graded using the NOS system for observational, case-control and RCTs. Incidence rates were tabulated for the following groups: never infected (NI) and unvaccinated (UV), NI and vaccinated (V), previously infected (PI) and UV, PI and V. Pooling were performed by grouping the RCTs and observational studies separately, and then all studies in total. Risk ratios and differences are reported for individual studies and pooled groups, in 1) NPI/V vs PI/UV and 2) PI/UV vs PI/V analysis. In addition, the number needed to treat (NNT) analysis was performed for vaccination in naïve and previously infected cohorts. Nine clinical studies were identified, including three randomized controlled studies, four retrospective observational cohorts, one prospective observational cohort, and a case-control study. The NOS quality appraisals of these articles ranged from four to nine (out of nine stars). All of the included studies found at least statistical equivalence between the protection of full vaccination and natural immunity; and, three studies found superiority of natural immunity. Four observational studies found a statistically significant incremental benefit to vaccination in the COVID-recovered individuals. In a total pooled analysis, the incidence in NPI/V trended higher than PI/UV groups (RR=1.86 [95%CI 0.77-4.51], P=0.17). Vaccination in COVID-recovered individuals provided modest protection from reinfection (RR=1.82 [95%CI 1.21-2.73], P=0.004), but the absolute risk difference was extremely small (AR= 0.004 person-years [95% CI 0.001-0.007], P=0.02). The NNT to prevent one annual case of infection in COVID-recovered patients was 218, compared to 6.5 in COVID-naïve patients, representing a 33.5-fold difference in benefit between the two populations. COVID-recovered individuals represent a distinctly different benefit-risk calculus. While vaccinations are highly effective at protecting against infection and severe COVID-19 disease, our review demonstrates that natural immunity in COVID-recovered individuals is, at least, equivalent to the protection afforded by complete vaccination of COVID-naïve populations. There is a modest and incremental relative benefit to vaccination in COVID-recovered individuals; however, the net benefit is marginal on an absolute basis. Therefore, vaccination of COVID-recovered individuals should be subject to clinical equipoise and individual preference., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Shenai et al.)

We found that an induction immunotherapy regimen consisting of rabbit anti-thymocyte globulin (Thymoglobulin) and the monoclonal antibody to CD20 rituximab (Rituxan) promoted long-term islet allograft survival in cynomolgus macaques maintained on rapamycin monotherapy. B lymphocyte reconstitution after rituximab-mediated depletion was characterized by a preponderance of immature and transitional cells, whose persistence was associated with long-term islet allograft survival. Development of donor-specific alloantibodies was abrogated only in the setting of continued rapamycin monotherapy.

The present study aimed to determine whether the frequency of double positive (DP) thymocytes expressing alphabeta T-cell receptor (TCR) clonotypes at the time of selection regulates peripheral CD4 T-cell compartment size. Scid recipients were inoculated with various ratios of TCR Calpha(0/0) and wild-type bone marrow (BM) stem cells. Increasing the frequency of TCR Calpha(0/0) thymocytes at steady-state introduced a graded decrease in the maturation probability of the total DP thymocyte pool. At 12-14 weeks following BM inoculation, the frequency of TCR Calpha(0/0) DP thymocytes was inversely correlated with that of CD4 single positive (SP) thymocytes. Notwithstanding, a decreased frequency of wild-type DP thymocytes led to a marked increase in their transit efficiency from the DP to SP compartments. The frequency-dependent increase in thymocyte transit efficiency was associated with a CD4 SP cell surface phenotype indicative of increased antigenic experience. Importantly, the frequency of DP thymocytes capable of expressing TCR clonotypes dictated the steady-state size of the peripheral CD4 T cell compartment and its potential for homeostatic proliferation. Collectively, these results indicate that the efficiency of DP to CD4 SP transit is a frequency dependent process, which determines (1) the steady-state size of the peripheral T cell compartment and (2) the threshold for homeostatic expansion of peripheral CD4 T cells.

Although it is well established that B-cells are required for the development of diabetes in the nonobese diabetic (NOD) mouse, the nature of their role remains unknown. Herein, we investigate the hypothesis that B-cells in this autoimmune background actively disrupt the tolerant state of those T-cells with which they interact. We demonstrate that NOD B-cells express elevated levels of crucial molecules involved in antigen presentation (including CD21/35, major histocompatibility complex class II, and CD40), alterations that invite the possibility of inappropriate T-cell activation. However, when chimeric animals are generated in which all B-cells are NOD-derived, a tolerant state is maintained. These data demonstrate that although B-cells are required for the development of autoimmunity, they are not sufficient to disrupt established tolerance. Moreover, non-B-cell antigen-presenting cells may be the critical actors in the establishment of the tolerant state; this function may be absent in NOD mice as they are characterized by deficient professional antigen-presenting cell function.

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.

Systemic lupus erythematosus (SLE) and the MRL-lpr/lpr murine model for SLE are characterized by the presence of serum anti-double-stranded (ds)DNA antibodies (Abs), whereas nonautoimmune individuals have negligible levels of these Abs. To increase the frequency of anti-DNA B cells and identify the mechanisms involved in their regulation in nonautoimmune mice, we have used Ig transgenes (tgs). In the present study, we used the VH3H9 heavy (H) chain tg which expresses an H chain that was repeatedly isolated from anti-dsDNA Abs from MRL-lpr/lpr mice. Because the VH3H9 H chain can pair with endogenous L chains to generate anti-single-stranded DNA, anti-dsDNA, and non-DNA B cells, this allowed us to study the regulation of anti-dsDNA B cells in the context of a diverse B cell repertoire. We have identified anti-dsDNA B cells that are located at the T-B interface in the splenic follicle where they have an increased in vivo turnover rate. These anti-dsDNA B cells exhibit a unique surface phenotype suggesting developmental arrest due to antigen exposure.