Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity

Dilip K. Challa, Wentao Mi, Su Tang Lo, Raimund J. Ober, E. Sally Ward

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.

Original languageEnglish (US)
JournalJournal of Autoimmunity
DOIs
StateAccepted/In press - Feb 19 2016

Fingerprint

Autoimmunity
T-Lymphocytes
Antigens
Immunoglobulin Fc Fragments
CD40 Ligand
Myelin Basic Protein
Autoimmune Experimental Encephalomyelitis
Autoimmune Diseases
Multiple Sclerosis
Epitopes
Hypersensitivity
Down-Regulation
Cell Count
Therapeutics

Keywords

  • Autoimmunity
  • CD4 T cells
  • EAE
  • Fc engineering
  • FcRn
  • Tolerance

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity. / Challa, Dilip K.; Mi, Wentao; Lo, Su Tang; Ober, Raimund J.; Ward, E. Sally.

In: Journal of Autoimmunity, 19.02.2016.

Research output: Contribution to journalArticle

Challa, Dilip K. ; Mi, Wentao ; Lo, Su Tang ; Ober, Raimund J. ; Ward, E. Sally. / Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity. In: Journal of Autoimmunity. 2016.
@article{9aff4731ee424d4da3a3f7f713875337,
title = "Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity",
abstract = "Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.",
keywords = "Autoimmunity, CD4 T cells, EAE, Fc engineering, FcRn, Tolerance",
author = "Challa, {Dilip K.} and Wentao Mi and Lo, {Su Tang} and Ober, {Raimund J.} and Ward, {E. Sally}",
year = "2016",
month = "2",
day = "19",
doi = "10.1016/j.jaut.2016.05.007",
language = "English (US)",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Antigen dynamics govern the induction of CD4+ T cell tolerance during autoimmunity

AU - Challa, Dilip K.

AU - Mi, Wentao

AU - Lo, Su Tang

AU - Ober, Raimund J.

AU - Ward, E. Sally

PY - 2016/2/19

Y1 - 2016/2/19

N2 - Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.

AB - Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3+ T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.

KW - Autoimmunity

KW - CD4 T cells

KW - EAE

KW - Fc engineering

KW - FcRn

KW - Tolerance

UR - http://www.scopus.com/inward/record.url?scp=84970002710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84970002710&partnerID=8YFLogxK

U2 - 10.1016/j.jaut.2016.05.007

DO - 10.1016/j.jaut.2016.05.007

M3 - Article

C2 - 27236506

AN - SCOPUS:84970002710

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

ER -