BACKGROUND:Belatacept-treated kidney transplant recipients (KT) experience a lower incidence of de novo donor-specific anti-HLA antibody (DSA) formation despite their higher risk of acute cellular rejection. In vitro studies show that concentrations associated with half-maximal suppression (EC50) of target cells correlate with therapeutic trough concentrations (C0). PURPOSE:To determine whether belatacept inhibits B-cell alloantigen presentation and B-cell alloresponse at known therapeutic C0. METHODS:Peripheral blood leukocytes (PBL) from healthy adults were cultured with HLA-mismatched PBL or fluorochrome-labeled alloantigenic lysate and increasing belatacept concentrations. EC50 was calculated with best-fit four-parameter log-logistic function under a Poisson assumption, as described. RESULTS:After overnight allostimulation, frequencies of alloreactive CD154 + B-cells and their subsets decreased with increasing belatacept concentrations (n = 10). Median (range) EC50s were 1.3 (0.01-37) µg/ml for unfractionated B-cells, 2 (0.03-50) µg/ml for naïve, 3.6 (0.2-92) µg/ml for unswitched memory, 6.2 (0.05-32) µg.ml for transitional, and 7.8 (0.01-101) µg/ml for plasmablasts. Median EC50s were highest at 19 and 31 µg/ml, respectively for CD27- and CD27 + isotype-switched memory B-cells. No effect was seen on B-cell presentation of alloantigen. CONCLUSIONS:At lower C0 levels of < 10 µg/ml, belatacept suppresses alloresponses of B-cells and most B-cell subsets, thereby explaining lower levels of DSA in kidney transplant patients.

Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URDHCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapsefree survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy-based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT.

Severe asthma with fungal sensitization (SAFS) is a subtype of asthma with high incidence in which patients are often therapy-resistant and have chronic disease features such as airway wall remodeling. Shared embryonic, immunologic, and microbiomic lineages of the gut-lung axis should be considered in disease pathogenesis investigations. A resistin family hormone, RELM-β, has been implicated in regulation of mucus production, immune responses, and bacterial colonization in the gut. RELM-β has been previously shown to increase macrophagic inflammation, goblet cell (GC) metaplasia, and fibrosis in mouse models. Since fungal asthma has unique early- and late-phase responses, we investigated the functions of RELM-β in our well-established model of SAFS utilizing Retnlb-null (KO) mice. Characteristics of SAFS developed in KO mice with some differences from wild-type (WT) controls. Kinetics of airway inflammation were delayed in KO although tissue inflammation was similar to WT. GCs interspersing the bronchial epithelia were similar, however, hyperexpression of Muc5ac and Muc5b in KO mice suggests of an altered mucin composition. Subepithelial fibrosis and airway resistance were markedly increased at late timepoints in KO mice compared to WT, indicating that RELM-β inhibits lung fibrosis. RELM-β may function as a homeostatic regulator of B cells since naïve KO mice had elevated systemic IgA. Related molecule, RELM-α, did not increase in KO mice although antimicrobial peptide Camp, Il13, and Tlr4 were hyperexpressed in lungs of these mice. Cumulatively, these data suggest that RELM-β is a regulator of allergic responses and that these effects may occur through direct/indirect mechanisms.

Asthma is characterized by inflammation and architectural changes in the lungs. A number of immune cells and mediators are recognized as initiators of asthma, although therapeutics based on these are not always effective. The multifaceted nature of this syndrome necessitate continued exploration of immunomodulators that may play a role in pathogenesis. We investigated the role of resistin-like molecule-beta (RELM-β), a gut antibacterial, in the development and pathogenesis of Aspergillus -induced allergic airways disease. Age and gender matched C57BL/6J and Retnlb −/− mice rendered allergic to Aspergillus fumigatus were used to measure canonical markers of allergic asthma at early and late time points. Inflammatory cells in airways were similar, although Retnlb −/− mice had reduced tissue inflammation. The absence of RELM-β elevated serum IgA and pro-inflammatory cytokines in the lungs at homeostasis. Markers of chronic disease including goblet cell numbers, Muc genes, airway wall remodelling, and hyperresponsiveness were greater in the absence RELM-β. Specific inflammatory mediators important in antimicrobial defence in allergic asthma were also increased in the absence of RELM-β. These data suggest that while characteristics of allergic asthma develop in the absence of RELM-β, that RELM-β may reduce the development of chronic markers of allergic airways disease.