Anti-RORC (internal region) polyclonal antibody

Objectives: To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon beta-1 alpha (IFN-beta-1 alpha). Methods: Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-beta-1 alpha for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively. Results: Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22-expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22-producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-beta-1 alpha induced reductions in transcription factor AHR, T-bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD41 cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR. Conclusions: Findings indicate that IFN-beta-1 alpha suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination. Classification of evidence: This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-beta-1 alpha treatment in patients with RRMS.

With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3 zeta chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of T(H)17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-gamma and T-bet, consistent with a T(H)17/T(H)1 bipolarization. When transferred into mice with established tumors, T(H)17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1 BB-based CART cells. Thus, redirection of T(H)17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.