Inhibiting Drug Allergy with Engineered Small Molecules
Allergic reactions to drugs, such as penicillin, can occur when they covalently attach to carrier proteins and then, in turn, the complex binds IgE. In this issue, Deak et al. (p. 21) describe the inhibition of allergic responses to penicillin using specifically engineered covalent heterobivalent inhibitors (cHBI). cHBIs were engineered to irreversibly bind Ag-specific IgE, as revealed by ELISA and flow cytometry. cHBI treatment was able to inhibit degranulation responses for allergen concentrations up to 2 μg/ml and reduced the allergic reaction of mice sensitized with drug allergens. This inhibition was both time and dose dependent, with inhibition lasting at least 72 h. Additionally, mice sensitized to drug allergen and treated prophylactically with cHBIs demonstrated resistance to allergic reaction 16 h after treatment. These data indicate that cHBIs can specifically reduce allergic reactivity toward known drug allergens and, therefore, provide a promising clinical avenue for the treatment of drug allergy.
Thymus-Derived, Bone Marrow to Thrive
Whereas mainstream αβT cells develop in the thymus via TCR-mediated selection, the involvement of coreceptors in the selection of minor T cell subsets with invariant TCRs remains elusive. In this issue, Yamamoto et al. (p. 167) found unexpectedly higher (10–15%) proportions of resident double negative T cells in bone marrow (BM) than what was seen in other lymphoid tissues of healthy adult mice. BM-resident DN αβT (BMDNT) cells displayed a diverse TCR repertoire and were thus distinct from known invariant NKT cells. Development of BMDNT cells was dependent on the thymic Notch ligand and IL-7, and was independent of MHC class II, β2-microglobulin–associated MHC class I, CD1d, or MR1. BMDNT cells became detectable after birth and were maintained by homeostatic proliferation through adulthood via myeloid cell–derived IL-1β. BMDNT cells also exhibited functional features of innate lymphoid cells, expressing a series of NK receptors and displaying potent cytotoxic activity and robust activation in the BM following systemic administration of TLR ligands. Together, these results suggest that a unique subset of αβT cells with innate immune function emerges after birth, develops in the thymus by TCR-based positive selection, and is sustained throughout adulthood in the BM.
Boosting Protection
The bacillus Calmette–Guérin (BCG) vaccine is a live, attenuated vaccine used to prevent tuberculosis. Recent studies have shown that expression of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of JAK/STAT signaling, is induced during BCG vaccination and may negatively affect the vaccine’s efficacy in protecting against Mycobacterium tuberculosis. In this issue, Mizuno et al. (p. 188) engineered a recombinant BCG secreting a dominant negative mutant of the SOCS1 molecule (rBCG-SOCS1DN). Mice immunized with this vaccine generated M. tuberculosis–specific T cell responses, and produced higher levels of IL-6, TNF-α, and IFN-γ. rBCG-SOCS1DN–vaccinated mice were better protected against M. tuberculosis challenge than mice vaccinated with a control BCG vaccine. These results indicate that a modified BCG vaccine which targets SOCS1 may be a viable approach to improving vaccine efficacy.
Antagonist against Lupus
The CD40/CD40L pathway is critical to humoral and cell-mediated immunity and has been linked to multiple pathological conditions associated with systemic lupus erythematosus (SLE). In this issue, Perper et al. (p. 58) developed a rat/mouse chimeric anti-mouse CD40 mAb. Anti-CD40 mAb treatment of mice with existing SLE symptoms significantly reduced severe proteinuria and nephritis and improved survival. However, SLE symptoms returned upon cessation of anti-CD40 mAb treatment, and the therapeutic effect of this mAb on reducing kidney inflammation was dose dependent. Not only did this CD40 antagonist reduce kidney glomerular disease, tubular dilation, and perivascular infiltration, but it was also associated with reduced salivary gland inflammation and restored saliva production. Together, these results indicate that treatment of mice with a CD40 antagonist can improve symptoms associated with murine SLE, which may inform the future development of CD40 antagonists for treating the disease in humans.
- Copyright © 2019 by The American Association of Immunologists, Inc.
