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Neutralization Versus Reinforcement of Proinflammatory Cytokines to Arrest Autoimmunity in Type 1 Diabetes

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Abstract

As physiological pathways of intercellular communication produced by all cells, cytokines are involved in the pathogenesis of inflammatory insulitis as well as pivotal mediators of immune homeostasis. Proinflammatory cytokines including interleukins, interferons, transforming growth factor-β, tumor necrosis factor-α, and nitric oxide promote destructive insulitis in type 1 diabetes through amplification of the autoimmune reaction, direct toxicity to β-cells, and sensitization of islets to apoptosis. The concept that neutralization of cytokines may be of therapeutic benefit has been tested in few clinical studies, which fell short of inducing sustained remission or achieving disease arrest. Therapeutic failure is explained by the redundant activities of individual cytokines and their combinations, which are rather dispensable in the process of destructive insulitis because other cytolytic pathways efficiently compensate their deficiency. Proinflammatory cytokines are less redundant in regulation of the inflammatory reaction, displaying protective effects through restriction of effector cell activity, reinforcement of suppressor cell function, and participation in islet recovery from injury. Our analysis suggests that the role of cytokines in immune homeostasis overrides their contribution to β-cell death and may be used as potent immunomodulatory agents for therapeutic purposes rather than neutralized.

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Abbreviations

AICD:

Activation-induced cell death

APC:

Antigen-presenting cells

CFA:

Complete Freund adjuvant

FasL:

Fas-ligand

GAD:

Glutamic acid decarboxylase

iNOS:

Inducible nitric oxide synthase

IFN:

Interferon

IL:

Interleukin

MHC:

Major histocompatibility complex

MIP-1α:

Macrophage inflammatory protein-1α

MCP-1:

Monocyte chemotactic protein-1

NO:

Nitric oxide

NFkB:

Nuclear factor-kB

nTreg:

Naturally occurring Treg

sFasL:

Soluble FasL

Th:

T helper cell

TNF:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

Treg:

Regulatory T cell

TGF-β:

Transforming growth factor-β

T1D:

Type 1 diabetes

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  1. The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202

    Ayelet Kaminitz, Shifra Ash & Nadir Askenasy

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  1. Ayelet Kaminitz
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Kaminitz, A., Ash, S. & Askenasy, N. Neutralization Versus Reinforcement of Proinflammatory Cytokines to Arrest Autoimmunity in Type 1 Diabetes. Clinic Rev Allerg Immunol 52, 460–472 (2017). https://doi.org/10.1007/s12016-016-8587-y

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