Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes

doi:10.1073/pnas.221220998

Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes

^*Division of Immunology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands; and ^†Department of Neurology, University of Tübingen, 72076 Tübingen, Germany

Edited by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, and approved August 23, 2001 (received for review May 4, 2001)

Abstract

The invariant chain (Ii) binds to newly synthesized MHC class II molecules with the CLIP region of Ii occupying the peptide-binding groove. Here we demonstrate that recombinant Ii proteins with the CLIP region replaced by antigenic self-epitopes are highly efficient in activating and silencing specific T cells in vitro and in vivo. The Ii proteins require endogenous processing by antigen-presenting cells for efficient T cell activation. An Ii protein encompassing the epitope myelin basic protein amino acids 84–96 (Ii-MBP84–96) induced the model autoimmune disease experimental allergic encephalomyelitis (EAE) with a higher severity and earlier onset than the peptide. When applied in a tolerogenic manner, Ii-MBP84–96 abolished antigen-specific T cell proliferation and suppressed peptide-induced EAE more effectively than peptide alone. Importantly, i.v. administration of Ii proteins after EAE induction completely abrogated the disease, whereas peptides only marginally suppressed disease symptoms. Ii fusion proteins are thus more efficient than peptide in modulating CD4⁺ T cell-mediated autoimmunity, documenting their superior qualities for therapeutic antigen delivery in vivo.

Footnotes

↵ ‡ F.B. and W.W. contributed equally to this work.
↵ § To whom reprint requests should be addressed at: Department of Neurology, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany. E-mail: felix.bischof{at}uni-tuebingen.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Ii,

invariant chain;

MBP,

myelin basic protein;

EAE,

experimental allergic encephalomyelitis;

PLP,

proteolipid protein;

IFA,

incomplete Freund's adjuvant;

CFA,

complete Freund's adjuvant;

PPD,

purified protein derivative