Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation

O’Sullivan, Brendan J., Pai, Saparna, Street, Shayna, An, Xiayou, MacDonald, Kelli P.A., Wong, Michele, Strutton, Geoffrey, Gerondakis, Steve, Steptoe, Raymond J., Fazekas de St. Groth, Barbara, Hill, Geoffrey R., and Thomas, Ranjeny (2011) Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation. Journal of Immunology, 187 (8). pp. 4018-4030.

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Abstract

Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (TEMs), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control TEMs and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive TEMs, and dysfunctional Foxp3+ regulatory T cells (Tregs) cells and conventional DCs. TEMs were regulated by Foxp3+ Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of TEM and Foxp3+ Treg IFN-γ production, as well as induction of IDO by host APCs. IDO was required for regulation of TEMs and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid TEM activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-γ, and IDO-dependent immune regulation. IFN-γ and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.

Item ID: 49534
Item Type: Article (Research - C1)
ISSN: 1550-6606
Date Deposited: 11 Jul 2017 01:38
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060111 Signal Transduction @ 34%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 33%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 33%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 34%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 33%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 33%
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