Targeting Memory T Cells in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

“…In a multicenter, randomized, double-blind, placebo-controlled clinical trial of recent onset T1D patients, treatment with alefacept, preserved their C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at one year, even after one year of termination of therapy. As expected, alefacept treatment in this study, significantly depleted CD4 + and CD8 + central memory T cells (Tcm) and effector memory T cells (Tem), preserved Tregs, increased the ratios of Treg to Tem and Tcm, and increased the percentage of PD-1 expressing CD4 + Tem and Tcm [20,21]. Preservation of Tregs, was the major finding in the T1DAL trial, and was plausibly due to the lower expression of CD2 on Tregs compared to the higher levels on memory T cells.…”

“…Alefacept has not only been used for the treatment of psoriasis but was successfully repurposed for other diseases that involved T cell activation such as type I diabetes (T1D) [20,21], preconditioning in allogeneic hematopoietic stem cell transplantation (HSCT) of pediatric patients with life-threatening nonmalignant diseases [22], kidney and liver transplantation [23][24][25], atopic dermatitis (AD) [26,27],…”

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

“…Various studies have indicated that Tm cells confer resistance to traditional immunosuppression, are difficult to eliminate by depletion therapies and have limited dependence on co-stimulatory blockage strategies (32,33). Hence, the present study adopted a strategy of applying anti-CXCL10 antibodies alone.…”

Strategies for clinical trials in type 1 diabetes

“…However, progress has been hampered by lack of direct access to the site of pathology, limitations of peripheral blood assays, and non-standardized immunologic assessments. Nevertheless, results from recent trials indicate that improved technologies and use of standardized mechanistic assessments can yield new insights into the pathology, progression, and treatment of T1D [7,57]. Fig.…”

“…Although autoreactive T cells can also be detected in the peripheral blood of healthy subjects, the hallmark of autoreactive T cells in T1D is their memory phenotype [57]. However, frequencies of autoreactive T cells in peripheral blood are low and available technologies are not sensitive enough to be practical in the clinical trial setting and blood volume constraints.…”