Altering immune tolerance therapeutically: the power of negative thinking

Abstract

The etiology of most human autoimmune diseases remains largely unknown. However, investigators have identified several negative regulatory mechanisms acting at the level of innate and/or adaptive immunity. Mutations resulting in a deficiency of some key regulatory molecules are associated with systemic or organ-specific inflammatory disorders, which often have a prominent autoimmune component. Genetic studies have implicated the negative regulator cytotoxic T-lymphocyte antigen 4 (CTLA-4) and other regulatory molecules in human autoimmune diseases. In addition to CTLA-4, key inhibitory molecules include programmed death 1 and B and T lymphocyte attenuator. Transforming growth factor beta1 and interleukin-10 also play major anti-inflammatory and regulatory roles. Tumor cells and infectious agents use negative regulatory pathways to escape immunity. The therapeutic blockage of negative signaling (particularly of CTLA-4) increases immunity against tumor antigens but also induces or aggravates autoimmune diseases. It appears that under normal conditions, the immune system is under strong "negative influences" that prevent autoimmunity and that release of this suppression results in disease. Regulation involves communication between the immune system and nonlymphoid tissues, and the latter can deliver inhibitory or stimulatory signals. Recent studies reveal that the generation of negative signals by selective engagement of inhibitory molecules is feasible and is likely to be of therapeutic benefit in autoimmune diseases and allograft rejection.

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

“…However, B-cell stimulation can be prevented by co-ligating inhibitory receptors. [60][61][62][63] We postulate that B cell reactivity to GLP-1 will be prevented or diminished when this peptide is fused to an Fc segment, through binding of this Fc segment to the FcgRIIB receptor. This is consistent with the tolerogenic effects of IgG carrier proteins, as demonstrated extensively in many studies.…”

Plasmid-based gene therapy of diabetes mellitus

“…This includes the expression of immunoinhibitory molecules by T cells, such as CTLA-4 and PD-1, and the production of regulatory cytokines, such as transforming growth factor b (TGF-b) and interleukin 10 (IL-10) by either T cells or other cells. 21 Immunity is further controlled by various types of Tr cells. [25][26][27][28] They can be broadly divided into two subsets, that is, the natural Tr cells of CD4 + CD25 + Foxp3 + phenotype, which in humans constitute 2-3% of peripheral blood mononuclear cells and the stimulation-induced (or adaptive) Tr cells identified in various models of inflammation, alloreactivity or autoimmunity.…”

“…39 The negative regulator CTLA-4 is the most studied and possibly the most potent T-cell inhibitory molecule. 3,21 It is expressed by T cells after activation and, similar to the positive costimulatory molecule CD28, binds to B7-1 (CD80) and B7-2 (CD86) on the membrane of APCs. It then downregulates T-cell reactivity by mechanisms that Abbreviations: CYP, cyclophosphamide; GAD65, glutamic acid decarboxylase 65; GAD65-IgG-Fc, GAD65-segment construct fused to an IgGFc segment; HSP60, heat shock protein 60; Ins, insulin; Ins-GAD, preproinsulin-GAD65 fusion protein; LMCV, lymphocytic choriomeningitis virus; PIns, proinsulin; PPIns, preprosinsulin; sGAD55, secreted form of GAD, 55 kDa; spGAD65, secreted GAD65; TG RIP-B7, transgenic mice with islet-restricted expression of B7.1 under the control of the rat insulin promoter (RIP); TG RIP-LCMV, transgenic mice with isletrestricted expression of LMCV nucleoprotein under the control of the rat insulin promoter (RIP); Tr, regulatory T cells; vvGAD65, recombinant vaccinia virus expressing GAD65.…”

“…However, most autoimmune diseases appear to result from defects in peripheral tolerance. 21 Extrathymic mechanisms of tolerance are important because not all auto-reactive T cells are deleted in the thymus. Indeed, some potentially autoaggressive T cells (perhaps with low affinity for self-antigens) are normally released from the thymus and must be controlled by various mechanisms.…”

“…Numerous studies have confirmed that T1D in rodents and humans is a T-celldependent autoimmune disease, resulting from defects in immune tolerance and T cell regulation. 21,22 The mechanisms that regulate tolerance are complex and act at the level of both innate and adaptive immunity.…”