Enhanced auto-antibody production and Mott cell formation in FcμR-deficient autoimmune mice

Characterization of FcμR deficiency in lupus-prone mic

Comparison of Immunologic Assays for Detecting Immune Responses in HIV Immunotherapeutic Studies: AIDS Clinical Trials Group Trial A5181▿

This study was designed to evaluate which of several T-cell-specific, immune response assays are the most relevant in measuring the key characteristics of an effective immune response to HIV-1. Using 5 HIV-1 antigens as stimulants, we assessed lymphocyte proliferation, supernatant gamma interferon (IFN-γ) cytokine production (CP), single-cell IFN-γ production by enzyme-linked immunospot (ELISPOT) assay, with and without Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs), and intracellular cytokine production (ICC) for IFN-γ and interleukin 2 (IL-2) by flow cytometry. We used these to compare specimens from HIV-1-infected subjects who were virally suppressed with a stable antiretroviral therapy (ART) regimen (group A) with specimens from subjects not on ART but with HIV-1 viremia of <3,000 copies/ml (group B). The lymphocyte proliferation assay (LPA) did not significantly differentiate between the two groups. Using fresh peripheral blood mononuclear cells (PBMCs), the CP and ELISPOT assays for IFN-γ detected the greatest differences between the two groups, specific for three of the five HIV-1 antigens, whereas significant differences were seen only in response to one antigen when cryopreserved cells were used. The strongest correlations were seen between the CP and ELISPOT assays. The ELISPOT B-LCL assay showed a cell concentration-dependent increase in IFN-γ production compared to that shown by the standard ELISPOT assay but did not differentiate between the groups. In the ICC assay, greater numbers of IFN-γ-producing T cells were seen in group B, and little or no detectable IL-2 production was seen in both groups. These studies highlight complexities of immunologic monitoring of T-cell responses in multisite clinical trials in HIV infection and outline considerations for optimizing these efforts

An open-label, multiple ascending dose study of the anti-CTLA-4 antibody ipilimumab in viremic HIV patients

<div><p>Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell function, is increased in chronic HIV-1 infection. It was hypothesized that CTLA-4 blockade may enhance immune response to HIV-1 and result in better control of viremia. This open-label, multiple ascending dose study (NCT03407105)—the first to examine ipilimumab in participants with HIV-1 infection—assessed the safety, tolerability, and pharmacokinetics of ipilimumab, as well as whether ipilimumab enhanced immune response to HIV-1 and improved control of viremia. Twenty-four participants received 2 or 4 doses of ipilimumab (0.1, 1, 3, or 5 mg/kg) every 28 days. No serious adverse events (AEs) or dose-limiting toxicities were reported; one participant discontinued ipilimumab for an AE of grade 2 facial palsy. Twenty participants (83.3%) had ≥1 AE; all but 1 were grade 1 or 2. Eight participants (33.3%) had potentially immune-related AEs (7 had grade 1 diarrhea not requiring corticosteroids; 1 who had diarrhea also had transient antinuclear antibody positivity; 1 had grade 2 facial palsy requiring corticosteroids). Two participants (8.3%), one each in the 0.1- and 1-mg/kg dose groups, had a decrease from baseline HIV-1 RNA of 0.85 and 1.36 log₁₀ copies/mL. Fourteen participants (58.3%) had an increase from baseline HIV-1 RNA (mean, 0.87 log₁₀ copies/mL; range, 0.59–1.29). Of these 14 participants, all but 1 were in the higher ipilimumab dose groups (3 or 5 mg/kg). No pattern was noted regarding change from baseline in CD4 or CD8 T cells; ex vivo assessments of immune response were precluded because of inadequate cell viability. Serum concentration data for ipilimumab showed biphasic disposition, with steady state reached by dose 3. Ipilimumab treatment was well tolerated and was associated with variations in HIV-1 RNA in excess of expected repeat measures in most participants, but these were not related to combination antiretroviral therapy status or CD4 counts. The mechanism(s) underlying the increased variation in HIV-1 RNA is unclear and needs further study.</p></div

Participant disposition.

<p>Participant disposition.</p

Adverse events reported in ≥4% of participants (total).

<p>Adverse events reported in ≥4% of participants (total).</p

Data for the participants with the maximum increase or decrease in HIV-1 RNA from baseline.

<p><b>(A)</b> Participant A (ipilimumab 1 mg/kg, 2 doses); <b>(B)</b> Participant B (ipilimumab 3 mg/kg, 4 doses).</p