Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes

Abstract

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype

“…Although activation of regulatory mechanisms capable of suppressing harmful autoreactive responses is a desired effect of antigen-specific immunotherapies ( 60 ), this hypothesis has been generated from experimental animal models but has not yet been demonstrated in humans so far. Deep phenotyping of major immune cell populations in a previous pilot trial showed that the immunomodulatory effect of GAD-alum injections into the lymph nodes did no induced any effect on Tregs, in line with results from previous studies ( 12 , 61 – 63 ). Changes induced by the treatment included instead expansion of follicular helper T cells (Tfh), and enhancement of CD8+ T cells with Th2 phenotype in parallel to increased exhausted CD8+T cells ( 61 ).…”

Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes

“…(GAD-alum) delays the progression of T1D with immunomodulatory effects including increased PD-1+ CD69+ cells in both CD8+ and double negative T cells (109,110). Apart from CTLA-4 and PD-1, the next wave of coinhibitory immune checkpoint receptor targets, including Lag-3, Tim-3, and TIGIT, are drawing increasing attention in clinical application.…”

“…Low-molecular-weight dextran sulfate reduces the incidence of diabetes and even reverses diabetes in early-onset diabetic NOD mice, at least partly via increasing PD-1 expression in T cells, reducing interferon-γCD4 and CD8 T cells, and enhancing the number of FoxP3 cells ( 107 , 108 ). Intralymphatic injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) delays the progression of T1D with immunomodulatory effects including increased PD-1+ CD69+ cells in both CD8+ and double negative T cells ( 109 , 110 ).…”

Prosopis strombulifera aqueous extract reduces T cell response and ameliorates type I diabetes in NOD mice

“…Experimental approaches for improving T cell mediated diseases have been considerably developed in the last years. 1 Available treatments for autoimmune diseases are based on immunosuppressant drugs, such as methylprednisolone, azathioprine, hydroxychloroquine and mycophenolate mofetil; however, these therapies may not always have the desired efficiency. 2 The use of these drugs significantly improves the clinical output of illnesses but they are also associated with considerable side effects, such as major risks to infections, gonadal failure and bone marrow depression.…”