Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2: Implications for gene therapy

Christoph M. Lanschuetzer, Edit B. Olasz, Zelmira Lazarova, Kim B. Yancey

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 ≥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.

Original languageEnglish (US)
Pages (from-to)1203-1207
Number of pages5
JournalJournal of Investigative Dermatology
Volume129
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Gene therapy
CD40 Ligand
Grafts
Genetic Therapy
Transplants
Immunoglobulin G
Skin
T-cells
Peripheral Tolerance
T-Lymphocytes
Bullous Pemphigoid
Adoptive Transfer
collagen type XVII
Basement Membrane
Cricetinae
Genes
Tissue
Antigens

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2 : Implications for gene therapy. / Lanschuetzer, Christoph M.; Olasz, Edit B.; Lazarova, Zelmira; Yancey, Kim B.

In: Journal of Investigative Dermatology, Vol. 129, No. 5, 05.2009, p. 1203-1207.

Research output: Contribution to journalArticle

@article{6ed4f234de7d4e48887e93e3c56d643d,
title = "Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2: Implications for gene therapy",
abstract = "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 ≥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 = "Lanschuetzer, {Christoph M.} and Olasz, {Edit B.} and Zelmira Lazarova and Yancey, {Kim B.}",
year = "2009",
month = "5",
doi = "10.1038/jid.2008.364",
language = "English (US)",
volume = "129",
pages = "1203--1207",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2

T2 - Implications for gene therapy

AU - Lanschuetzer, Christoph M.

AU - Olasz, Edit B.

AU - Lazarova, Zelmira

AU - Yancey, Kim B.

PY - 2009/5

Y1 - 2009/5

N2 - 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 ≥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.

AB - 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 ≥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.

UR - http://www.scopus.com/inward/record.url?scp=65049084893&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65049084893&partnerID=8YFLogxK

U2 - 10.1038/jid.2008.364

DO - 10.1038/jid.2008.364

M3 - Article

C2 - 19037236

AN - SCOPUS:65049084893

VL - 129

SP - 1203

EP - 1207

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 5

ER -