Regulatory T Cells in Severe Persistent Asthma in the Era of Monoclonal Antibodies Target Therapies.

Asthma is an immunoinflammatory disease characterized by bronchial hyper-reactivity to different external stimuli. New monoclonal target treatments have been developed, but few studies have investigated the role of regulatory T cells in severe asthma and the modulatory effect of biological therapy on regulatory T cell functions. Their dysfunction may contribute to the development and exacerbation of asthma. Here we review the recent literature on the potential immunological role of regulatory T cells in the pathogenesis of severe asthma. The analysis of the role of regulatory T cells was performed in terms of functions and their possible interactions with mechanisms of action of the novel treatment for severe asthma. In an era of biological therapies for severe asthma, little data is available on the potential effects of what could be a new therapy: monoclonal antibody targeting of regulatory T cell numbers and functions.

Induction Type and Outcomes in HLA-DR Mismatch Kidney Transplantation.

BACKGROUND: In kidney transplantation, donor recipient human leukocyte antigen (HLA)-DR mismatch signals high immunologic risk and portends inferior outcomes. We compared the impacts of depleting vs non-depleting antibody induction on the outcomes in kidney transplant recipients (KTRs) at different levels of HLA-DR mismatches. METHODS: Using the Organ Procurement and Transplantation Network/United Network for Organ Sharing database, we identified adult KTRs from 2001 to 2015 who received induction therapy with either depleting (thymoglobulin/alemtuzumab) or non-depleting (basiliximab/daclizumab) antibody and were discharged on calcineurin inhibitor/mycophenolic acid maintenance. Patients were then stratified by the number of donor-recipient HLA-DR mismatches (0, 1, 2) in both living donor (LD) and deceased donor (DD) KTRs. Under each HLA-DR mismatch category, long-term outcomes were compared for depleting vs non-depleting induction using a Cox model. RESULTS: A total of 63,821 LD (HLA-DR mismatches: 0, n = 6945 [depleting = 4409, non-depleting = 2536]; 1, n = 19,557 [depleting = 13,558, non-depleting = 6019]; and 2, n = 10,727 [depleting = 7694, non-depleting = 3033]) and 64,922 DD (HLA-DR mismatches: 0, n = 13,915 [depleting = 10,124, non-depleting = 3791]; 1, n = 27,994 [depleting = 20,454, non-depleting = 7540]; and 2, n = 23,013 [depleting = 16,908, non-depleting = 6105]) KTRs were included in the analysis. Adjusted patient death risk was significantly lower in the depleting vs non-depleting antibody induction group among DD kidney recipients (hazard ratio 0.90, 95% CI 0.85-0.96, P = .001) and trended lower among LD kidney recipients (HR 0.88, 95% 0.79-1.01, P = .05) with 2 HLA-DR mismatches. DISCUSSION: Our study found a patient survival benefit associated with the use of perioperative induction with depleting when compared to non-depleting antibody in KTRs with 2 HLA-DR mismatches and maintained on a calcineurin inhibitor/mycophenolic acid regimen.

Design, creation and in vitro testing of a reduced immunogenicity humanized anti-CD25 monoclonal antibody that retains functional activity.

Humanized and fully human sequence-derived therapeutic antibodies retain the capacity to induce anti-drug antibodies. Daclizumab (humanized version of the murine anti-Tac antibody; E.HAT) was selected for a proof of concept application of engineering approaches to reduce potential immunogenicity due to its demonstrated immunogenicity in the clinic. Reduced immunogenicity variants of E.HAT were created by identifying and modifying a CD4+ T cell epitope region in the VH region. Variant epitope region peptides were selected for their reduced capacity to induce CD4+ T cell proliferative responses in vitro. Variant antibody molecules were created, and CD25 affinity and potency were similar to the unmodified parent antibody. Fab fragments from the variant antibodies induced a lower frequency and magnitude of responses in human peripheral blood mononuclear cells proliferation tests. By the empirical selection of two amino acid mutations, fully functional humanized E.HAT antibodies with reduced potential to induce immune responses in vitro were created.