Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2: implications for gene therapy.
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.
Lanschuetzer
Christoph M
CM
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconcin, USA. c.lanschuetzer@salk.at
Olasz
Edit B
EB
Lazarova
Zelmira
Z
Yancey
Kim B
KB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004820:Epidermolysis Bullosa / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024041:Non-Fibrillar Collagens / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D000097805:Collagen Type XVII
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D019013:CD40 Antigens; D023201:CD40 Ligand; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C499308:Rag2 protein, mouse