First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes

: Background : Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. Methods: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. Results: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change − 0.108, − 0.041, − 0.040, and − 0.012, respectively), suggesting no disease progression. Conclusions: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016–003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018–003728-35

H5N1 Influenza Vaccine Formulated with AS03A Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses

Objective Adjuvantation of an H5N1 split-virion influenza vaccine with AS03(A) substantially reduces the antigen dose required to produce a putatively protective humoral response and promotes cross-clade neutralizing responses. We determined the effect of adjuvantation on antibody persistence and B- and T-cell-mediated immune responses. Methods Two vaccinations with a split-virion A/Vietnam/1194/2004 (H5N1, clade 1) vaccine containing 3.75-30 mu g hemagglutinin and formulated with or without adjuvant were administered to groups of 50 volunteers aged 18-60 years. Results Adjuvantation of the vaccine led to better persistence of neutralizing and hemagglutination-inhibiting antibodies and higher frequencies of antigen-specific memory B cells. Cross-reactive and polyfunctional H5N1-specific CD4 T cells were detected at baseline and were amplified by vaccination. Expansion of CD4 T cells was enhanced by adjuvantation. Conclusion Formulation of the H5N1 vaccine with AS03(A) enhances antibody persistence and induces stronger T- and B-cell responses. The cross-clade T-cell immunity indicates that the adjuvanted vaccine primes individuals to respond to either infection and/or subsequent vaccination with strains drifted from the primary vaccine strain

Activation et inactivation des lymphocytes T :implications immunothérapeutiques

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Induction of long-term but reversible unresponsiveness after activation of murine T cell hybridomas.

T cell receptor (TCR)-mediated stimulation of murine T cell hybridomas induces cell activation and lymphokine production. We have observed that following productive activation, T cell hybridomas become refractory to a subsequent stimulation. Hyporesponsiveness is long-lasting but reversible, and is not due to reduced receptor expression. It is noteworthy that hyporesponsiveness is cell autonomous, persists in spite of cell division and does not require continuous exposure to ligands. Hyporesponsive cells retain the ability to produce lymphokines in response to pharmacological agents bypassing receptor triggering, indicating that they possess a functional enzymatic machinery for interleukin 2 synthesis and secretion. Reduced phosphatidylinositol hydrolysis was observed in these cells in response to TCR stimulation, suggesting that hyporesponsiveness result from defective transduction of activation signals. The development of unresponsiveness following receptor stimulation resembles desensitization, and may thus play an important role in the regulation of an immune response and in the induction of immune tolerance.Journal Articleinfo:eu-repo/semantics/publishe

Tolerant CD8 T cells induced by multiple injections of peptide antigen show impaired TCR signaling and altered proliferative responses in vitro and in vivo

The mechanisms responsible for peripheral CD8 T cell tolerance to foreign Ags remain poorly understood. In this study we have characterized the state of CD8 T cell tolerance induced in F5 TCR transgenic mice by multiple peptide injections in vivo. The tolerant state of CD8 T cells is characterized by impaired proliferative responses, increased sensitivity to cell death, and failure to acquire cytotoxic effector function after in vitro antigenic challenge. In vivo monitoring of CD8 T cell proliferation using 5- carboxyfluorescein diacetate succinimidyl ester showed that a large subset of the tolerant T cell population failed to divide in response to peptide. TCR down-regulation could not account for this loss of responsiveness to Ag since recombination-activating gene-1 (RAG-1)(-/-)F5 CD8 T cell responses were similar to those of RAG-1(-/-)F5 x RAG-1(-/-)F1 T lymphocytes, which express lower levels of the transgenic TCR. Analysis of early signal transduction in tolerant CD8 T cells revealed high basal levels of cytoplasmic calcium as well as impaired calcium mobilization and tyrosine phosphorylation after cross-linking of CD3ε and CD8α. Together these data indicate that repeated exposure to soluble antigenic peptide in vivo can induce a state of functional tolerance characterized by defective TCR signaling, impaired proliferation, and increased sensitivity to cell death.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Treatment of murine B cell lymphoma with bispecific monoclonal antibodies (anti-idiotype x anti-CD3).

It has previously been reported that T lymphocytes can be targeted by using bispecific antibodies consisting of anti-target antibody and anti-CD3. In the present study, a bispecific mAb was developed by somatic hybridization of mouse hybridomas, one producing a mAb against the Id determinant of the mouse B cell lymphoma 38C13 and the other a mAb against a polymorphic determinant on murine CD3. The bispecific antibody, anti-38C13 x anti-CD3, is bi-isotypic (IgG1 x IgG2a) and was purified by ion exchange and affinity chromatography. The dual specificity of the hybrid hybridoma-produced mAb could be demonstrated by flow cytometry, the induction of T cell proliferation, the induction of IL-2 secretion by polyclonal T cells, and redirected lysis of the relevant target cells. The hybrid (bi-isotypic) Fc part of the bispecific antibodies was nonfunctional in FcR-dependent redirected lysis. In vivo studies demonstrate that this bispecific mAb could efficiently target T cells towards the tumor cells, resulting in long term survival and cure of the lymphoma.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Lack of T cell tolerance in mice exposed to a protein antigen through lactation.

Offspring of mother mice treated immediately after delivery with deaggregated human gamma-globulins (dHGG) are unable to produce HGG-specific antibodies when challenged with immunogenic forms of HGG (HGG/CFA) in adulthood. Despite a defective antibody response, animals rendered tolerant to HGG as neonates retain tolerogen-specific T cells able to proliferate and secrete lymphokines. The pattern of IL-2 and IL-4 secretion by T cells isolated from tolerant animals could not be distinguished from the corresponding cells in control mice, suggesting that neonatal exposure to dHGG did not affect T cell reactivity or Th1/Th2 in vivo balance. Moreover, immunization of tolerant animals with haptenated HGG confirmed the presence of tolerogen-specific helper T cells in vivo. Functional T cell depletion by anti-CD3 mAbs during lactation failed to modify induction of B cell tolerance, suggesting that T cells are neither affected nor required to induce the selective tolerance status observed in this model. Based on the finding that antigen-presenting cell functions in secondary organs (spleen, peritoneal cavity) are a late acquisition during ontogeny and reach adult-like levels at weaning, we propose that most soluble proteins elude T cell recognition during lactation due to defective antigen presentation.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Dendritic cells and macrophages induce the development of distinct T helper cell populations in vivo.

In VitroJournal Articleinfo:eu-repo/semantics/publishe

In vivo induction of IL-10 by anti-CD3 monoclonal antibody in mice.

Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Induction of Th2 responses to soluble proteins is independent of B cell tolerance status

Injection of high doses of monomeric human gamma globulins (dHGG) in naive, adult mice causes antigen-specific tolerance of B cell and T(h)1 lymphocytes, while inducing the selective expansion of antigen-specific T(h)2 cells. Several parameters of tolerance induction were analyzed in this work, in order to establish whether B cell tolerance and T(h)1 unresponsiveness were functionally related in this in vivo model. By varying the antigen form and site of injection, we demonstrate in this work that T(h)1 unresponsiveness to HGG is not a consequence of peripheral B cell tolerance. In particular, mice pretreated with heat-aggregated antigen (HAHGG) or F(ab')(2) HGG were found to develop a strong humoral response white displaying a defective T(h)1 response. In fact, these animals developed a strong T(h)2 response in vivo, demonstrating that selective expansion of antigen-specific T(h)2 cells in this model is not a consequence of B cell tolerance or antigen capture by Fc receptor-expressing cells. We conclude that while B cell tolerance in this model is only observed in response to deaggregated antigen, injection of all forms of adjuvant-free, protein antigens induces T helper precursor cells to differentiate into T(h)2-type helper cells in vivo irrespectively of the B cell tolerance status