Browsing by Subject "IFN-γ"

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    A Dose-escalation Study of Recombinant Human Interleukin-18 in Combination With Ofatumumab After Autologous Peripheral Blood Stem Cell Transplantation for Lymphoma
    (Wolters Kluwer, 2018-04) Robertson, Michael J.; Stamatkin, Christopher W.; Pelloso, David; Weisenbach, Jill; Prasad, Nagendra K.; Safa, Ahmad R.; Medicine, School of Medicine
    Interleukin-18 (IL-18) is an immunostimulatory cytokine that augments antibody-dependent cellular cytotoxicity mediated by human natural killer cells against antibody-coated lymphoma cells in vitro and that has antitumor activity in animal models. Ofatumumab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with ofatumumab was undertaken in patients with CD20 lymphoma who had undergone high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Cohorts of 3 patients were given intravenous infusions of ofatumumab 1000 mg weekly for 4 weeks with escalating doses of rhIL-18 as a intravenous infusion weekly for 8 consecutive weeks. Nine male patients with CD20 lymphomas were given ofatumumab in combination with rhIL-18 at doses of 3, 10, and 30 μg/kg. No unexpected or dose-limiting toxicities were observed. The mean reduction from predose levels in the number of peripheral blood natural killer cells after the first rhIL-18 infusion was 91%, 96%, and 97% for the 3, 10, and 30 μg/kg cohorts, respectively. Serum concentrations of interferon-γ and chemokines transiently increased following IL-18 dosing. rhIL-18 can be given in biologically active doses by weekly infusions in combination with ofatumumab after peripheral blood stem cell transplantation to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus ofatumumab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.
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    Regulatory T Cells Kinetics in Immune Reconstitution Inflammatory Syndrome in HIV-Tuberculosis Co-Infected Individuals
    (IMR Press, 2025) Barros, Nicolas; Sanchez, Cesar A.; White, A. Clinton, Jr.; Bauer, Allison; Woll, Fernando; Graviss, Edward A.; Seas, Carlos; Gotuzzo, Eduardo; Montes, Martin; Medicine, School of Medicine
    Background: Combination antiretroviral therapy (cART) can suppress human immunodeficiency virus (HIV-1) replication, but some patients develop worsening of co-infections, termed immune reconstitution inflammatory syndrome. Regulatory T cells (Tregs) are a population of CD4+ T cells that modulate immune responses. We hypothesized that immune reconstitution inflammatory syndrome (IRIS) is associated with Tregs dysfunction. Methods: We prospectively enrolled antiretroviral naive HIV patients with co-infection with Mycobacterium tuberculosis (MTB; N = 26) or controls with no prior opportunistic infection (N = 10). We prospectively measured HIV viral load, CD4+ T cell count, regulatory T cell (CD4high, CD127low-neg, Foxp3+) proportion, and Interferon-γ (IFN-γ) response to MTB peptides before and after initiation of combination antiretroviral therapy. Results: Eleven of the MTB patients developed IRIS; 15 did not. IRIS patients had a lower proportion of Tregs at baseline compared to no-IRIS patients (HIV/no-OI and HIV/MTB no-IRIS), but the difference did not reach statistical significance (IRIS: 9.6 [5.3-11.2]; no-IRIS: 13.9 [7.6-22.5] p = 0.066). After 2 weeks of cART the proportion of Tregs was significantly lower in HIV/MTB IRIS patients (HIV/MTB IRIS: 9.8 [6.6-13.6], HIV/MTB no-IRIS: 15.8 [11.1-18.8]. The antigen-specific IFN-γ production was greater in the patients who developed IRIS compared with those who did not develop IRIS. Conclusion: IRIS patients had a lower proportion of Tregs and more marked IFN-γ production, suggesting that Tregs may be responsible for suppressing the antigen-specific inflammatory response.
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    SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop
    (Oxford, 2017-04) Yu, Tingting; Zuo, Yong; Cai, Rong; Huang, Xian; Wu, Shuai; Zhang, Chenxi; Chin, Y. Eugene; Li, Dongdong; Zhang, Zhenning; Xia, Nansong; Wang, Qi; Shen, Hao; Yao, Xuebiao; Zhang, Zhong-Yin; Xue, Song; Shen, Lei; Cheng, Jinke; Biochemistry and Molecular Biology, School of Medicine
    Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK−STAT1 signaling. Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here, we identify a novel negative feedback loop mediated by STAT3−SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages. Accordingly, SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.