Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2: implications for gene therapy. J Invest Dermatol 2009 May;129(5):1203-7
Date
11/28/2008Pubmed ID
19037236Pubmed Central ID
PMC2681490DOI
10.1038/jid.2008.364Scopus ID
2-s2.0-65049084893 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
Skin grafts from mice expressing human bullous pemphigoid antigen 2 (hBPAG2) in epidermal basement membrane elicit hBPAG2-specific IgG and graft loss in wild-type (Wt) recipients. Graft loss was dependent on CD4+ T cells and correlated with the production and tissue deposition of hBPAG2-specific IgG. To explore the role of CD40/CD40 ligand (CD40L) interaction in this model, Wt mice grafted with transgenic (Tg) skin were treated with hamster anti-CD40L mAb MR1. In contrast to grafted Wt mice treated with equivalent doses of control IgG, 22 of 23 MR1-treated Wt mice did not develop hBPAG2-specific IgG or graft loss for >or=60 days. MR1-treated mice also accepted a second Tg skin graft without durable production of hBPAG2-specific IgG or graft loss. Moreover, splenocytes and enriched CD4+ T cells from MR1-treated graft recipients transferred un- or hyporesponsiveness to hBPAG2 to other mice and demonstrated a dominant tolerant effect over cotransferred naive splenocytes following adoptive transfer to Rag2-/- mice. Successful inhibition of hBPAG2-specific IgG production and Tg graft loss following CD40:CD40L co-stimulatory blockade in this model provides opportunities to study mechanisms of peripheral tolerance and generate antigen-specific regulatory CD4+ cells-issues of relevance to patients with pemphigoid as well as individuals undergoing gene replacement therapy for epidermolyis bullosa.
Author List
Lanschuetzer CM, Olasz EB, Lazarova Z, Yancey KBAuthor
Edit Olasz MD, PhD Associate Professor in the Dermatology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Autoantigens
Basement Membrane
CD40 Antigens
CD40 Ligand
DNA-Binding Proteins
Disease Models, Animal
Dose-Response Relationship, Drug
Epidermolysis Bullosa
Genetic Therapy
Humans
Immunoglobulin G
Immunoglobulin M
Lymphocytes
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Non-Fibrillar Collagens
Skin Transplantation
