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A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery

Autoimmune diseases such as rheumatoid arthritis are caused by immune system recognition of self-proteins and subsequent production of effector T cells that recognize and attack healthy tissue. Therapies for these diseases typically utilize broad immune suppression, which can be effective, but which...

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Autores principales: Goldberg, Shalom D., Felix, Nathan, McCauley, Michael, Eberwine, Ryan, Casta, Lou, Haskell, Kathleen, Lin, Tricia, Palovick, Elizabeth, Klein, Donna, Getts, Lori, Getts, Robert, Zhou, Mimi, Bansal-Pakala, Pratima, Dudkin, Vadim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540115/
https://www.ncbi.nlm.nih.gov/pubmed/34683962
http://dx.doi.org/10.3390/pharmaceutics13101669
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author Goldberg, Shalom D.
Felix, Nathan
McCauley, Michael
Eberwine, Ryan
Casta, Lou
Haskell, Kathleen
Lin, Tricia
Palovick, Elizabeth
Klein, Donna
Getts, Lori
Getts, Robert
Zhou, Mimi
Bansal-Pakala, Pratima
Dudkin, Vadim
author_facet Goldberg, Shalom D.
Felix, Nathan
McCauley, Michael
Eberwine, Ryan
Casta, Lou
Haskell, Kathleen
Lin, Tricia
Palovick, Elizabeth
Klein, Donna
Getts, Lori
Getts, Robert
Zhou, Mimi
Bansal-Pakala, Pratima
Dudkin, Vadim
author_sort Goldberg, Shalom D.
collection PubMed
description Autoimmune diseases such as rheumatoid arthritis are caused by immune system recognition of self-proteins and subsequent production of effector T cells that recognize and attack healthy tissue. Therapies for these diseases typically utilize broad immune suppression, which can be effective, but which also come with an elevated risk of susceptibility to infection and cancer. T cell recognition of antigens is driven by binding of T cell receptors to peptides displayed on major histocompatibility complex proteins (MHCs) on the cell surface of antigen-presenting cells. Technology for recombinant production of the extracellular domains of MHC proteins and loading with peptides to produce pMHCs has provided reagents for detection of T cell populations, and with the potential for therapeutic intervention. However, production of pMHCs in large quantities remains a challenge and a translational path needs to be established. Here, we demonstrate a fusion protein strategy enabling large-scale production of pMHCs. A peptide corresponding to amino acids 259–273 of collagen II was fused to the N-terminus of the MHC_II beta chain, and the alpha and beta chains were each fused to human IgG4 Fc domains and co-expressed. A tag was incorporated to enable site-specific conjugation. The cytotoxic drug payload, MMAF, was conjugated to the pMHC and potent, peptide-specific killing of T cells that recognize the collagen pMHC was demonstrated with tetramerized pMHC-MMAF conjugates. Finally, these pMHCs were incorporated into MMAF-loaded 3DNA nanomaterials in order to provide a biocompatible platform. Loading and pMHC density were optimized, and peptide-specific T cell killing was demonstrated. These experiments highlight the potential of a pMHC fusion protein-targeted, drug-loaded nanomaterial approach for selective delivery of therapeutics to disease-relevant T cells and new treatment options for autoimmune disease.
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spelling pubmed-85401152021-10-24 A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery Goldberg, Shalom D. Felix, Nathan McCauley, Michael Eberwine, Ryan Casta, Lou Haskell, Kathleen Lin, Tricia Palovick, Elizabeth Klein, Donna Getts, Lori Getts, Robert Zhou, Mimi Bansal-Pakala, Pratima Dudkin, Vadim Pharmaceutics Article Autoimmune diseases such as rheumatoid arthritis are caused by immune system recognition of self-proteins and subsequent production of effector T cells that recognize and attack healthy tissue. Therapies for these diseases typically utilize broad immune suppression, which can be effective, but which also come with an elevated risk of susceptibility to infection and cancer. T cell recognition of antigens is driven by binding of T cell receptors to peptides displayed on major histocompatibility complex proteins (MHCs) on the cell surface of antigen-presenting cells. Technology for recombinant production of the extracellular domains of MHC proteins and loading with peptides to produce pMHCs has provided reagents for detection of T cell populations, and with the potential for therapeutic intervention. However, production of pMHCs in large quantities remains a challenge and a translational path needs to be established. Here, we demonstrate a fusion protein strategy enabling large-scale production of pMHCs. A peptide corresponding to amino acids 259–273 of collagen II was fused to the N-terminus of the MHC_II beta chain, and the alpha and beta chains were each fused to human IgG4 Fc domains and co-expressed. A tag was incorporated to enable site-specific conjugation. The cytotoxic drug payload, MMAF, was conjugated to the pMHC and potent, peptide-specific killing of T cells that recognize the collagen pMHC was demonstrated with tetramerized pMHC-MMAF conjugates. Finally, these pMHCs were incorporated into MMAF-loaded 3DNA nanomaterials in order to provide a biocompatible platform. Loading and pMHC density were optimized, and peptide-specific T cell killing was demonstrated. These experiments highlight the potential of a pMHC fusion protein-targeted, drug-loaded nanomaterial approach for selective delivery of therapeutics to disease-relevant T cells and new treatment options for autoimmune disease. MDPI 2021-10-13 /pmc/articles/PMC8540115/ /pubmed/34683962 http://dx.doi.org/10.3390/pharmaceutics13101669 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Goldberg, Shalom D.
Felix, Nathan
McCauley, Michael
Eberwine, Ryan
Casta, Lou
Haskell, Kathleen
Lin, Tricia
Palovick, Elizabeth
Klein, Donna
Getts, Lori
Getts, Robert
Zhou, Mimi
Bansal-Pakala, Pratima
Dudkin, Vadim
A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title_full A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title_fullStr A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title_full_unstemmed A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title_short A Strategy for Selective Deletion of Autoimmunity-Related T Cells by pMHC-Targeted Delivery
title_sort strategy for selective deletion of autoimmunity-related t cells by pmhc-targeted delivery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540115/
https://www.ncbi.nlm.nih.gov/pubmed/34683962
http://dx.doi.org/10.3390/pharmaceutics13101669
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