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• W2045382802 abstract "alopecia areata antigen-presenting cell CD4, 8, 25, 80, and 86 antigen cytotoxic T-lymphocyte-associated protein 4 United States Food and Drug Administration human leukocyte antigen immunoglobulin G1 TO THE EDITOR Rodent models with autoimmune diseases provide many insights to unravel the complexities of human diseases as tools for hypothesis testing and preclinical drug efficacy screening (Sun et al., 2008Sun J. Silva K.A. McElwee K.J. et al.The C3H/HeJ mouse and DEBR rat models for alopecia areata: preclinical drug screening tools.Exp Dermatol. 2008; 17: 793-805Crossref PubMed Scopus (52) Google Scholar). Nearly 10 years ago, we performed a comparative mouse and human gene array study to identify potentially dysregulated genes in alopecia areata (AA). One such gene was Clta4, a co-stimulatory T-cell ligand that binds B7.1 (CD80) and B7.2 (CD86) on antigen-presenting cells (APCs) (Carroll et al., 2002Carroll J. McElwee K.J. King L.E. et al.Gene array profiling and immunomodulation studies define a cell mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.J Invest Dermatol. 2002; 119: 392-402Crossref PubMed Scopus (105) Google Scholar). As AA is an autoimmune disease in humans and mice, we hypothesized that CTLA4, through its co-stimulatory T cell and APC pathways, is a critical regulator of AA onset and maintenance, based on studies in the mouse model of AA (Sundberg et al., 1994Sundberg J.P. Cordy W.R. King L.E. Alopecia areata in aging C3H/HeJ mice.J Invest Dermatol. 1994; 102: 847-856Abstract Full Text PDF PubMed Google Scholar). We performed preclinical studies by intraperitoneally injecting mAbs against APC surface markers B7.1 (CD80) and B7.2 (CD86), and a monoclonal anti-CTLA4 antibody into C3H/HeJ mice with and without AA to disrupt T cell and APC interactions involving CTLA4. The studies conclusively showed that these mAbs effectively prevented onset of AA in the mouse model (Carroll et al., 2002Carroll J. McElwee K.J. King L.E. et al.Gene array profiling and immunomodulation studies define a cell mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.J Invest Dermatol. 2002; 119: 392-402Crossref PubMed Scopus (105) Google Scholar; Sun et al., 2008Sun J. Silva K.A. McElwee K.J. et al.The C3H/HeJ mouse and DEBR rat models for alopecia areata: preclinical drug screening tools.Exp Dermatol. 2008; 17: 793-805Crossref PubMed Scopus (52) Google Scholar). Subsequently, we confirmed increased numbers of skin-infiltrating cells and skin-draining lymph node cells in AA mice expressed CD80/86, whereas CTLA4 was increased in both populations; primarily on CD4+/CD25- cells (Zoller et al., 2002Zoller M. McElwee K.J. Engel P. et al.Transient CD44 variant isoform expression and reduction in CD4+/CD25+ regulatory T cells in C3H/HeJ mice with alopecia areata.J Invest Dermatol. 2002; 118: 983-992Crossref PubMed Scopus (70) Google Scholar). CTLA4 (CD152) was similarly found with significantly elevated expression in peripheral blood CD4+/CD25- cells of AA patients (Zoller et al., 2004aZoller M. McElwee K.J. Vitacolonna M. et al.Apoptosis resistance in perifpheral blood lymphocytes of alopecia areata patients.J Autoimmunity. 2004; 23: 241-256Crossref PubMed Scopus (25) Google Scholar), and a significantly larger percentage of peripheral blood mononuclear cells expressed CD80 (Zoller et al., 2004bZoller M. McElwee K.J. Vitacolonna M. et al.The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells.Exp Dermatol. 2004; 13: 435-444Crossref PubMed Scopus (27) Google Scholar). Recently, two landmark papers were published, the first a human genome-wide association study (Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome- wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar), and more recently, another that replicated CTLA4 as a major candidate gene for AA susceptibility in humans (John et al., 2011John K.K.-G. Brockschmidt F.F. Redler S. et al.Genetic variants in CTLA4 are strongly associated with alopecia areata.J Invest Dermatol. 2011; 131: 1169-1172Crossref PubMed Scopus (44) Google Scholar), providing exciting data on human AA and validating the first bona fide susceptibility locus outside the HLA. The co-stimulatory locus containing the CTLA4 gene on mouse chromosome 1 (human chromosome 2) was not previously identified as a quantitative trait locus in the mouse AA model (Sundberg et al., 2003Sundberg J.P. Boggess D. Silva K.A. et al.Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice.J Invest Dermatol. 2003; 120: 771-775Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, Sundberg et al., 2004Sundberg J.P. Silva K.A. Li R. et al.Adult onset alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model.J Invest Dermatol. 2004; 123: 294-297Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). However, the convergence of expression data from the AA model with the human studies confirm our hypothesis that antigen presentation in association with CTLA4–CD80/86 co-stimulation is implicated in the development of AA and provides a crucial foundation for future human clinical studies. For example, the preclinical data from the mouse AA model could be used to support testing of Abatacept (Orencia, Bristol-Myers Squibb, Corporate Headquarters, New York, NY), a drug approved by the United States Food and Drug Administration to treat autoimmune rheumatoid arthritis (Moreland et al., 2006Moreland L. Bate G. Kirkpatrick P. Abatacept.Nat Rev Drug Discov. 2006; 5: 185-186Crossref PubMed Scopus (144) Google Scholar), as a safe and effective therapy for human AA. Abatacept is a fusion protein with the extracellular domain of CTLA4 fused with the hinge CH2 and CH3 domains of human IgG1. It is a selective modulator that binds to the co-stimulatory protein CD28 on T cells and B7 proteins (CD80/CD86) on APCs. As a possible alternative, Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully humanized anti-CTLA4 mAb, United States Food and Drug Administration approved to treat metastatic melanoma; however, Ipilimumab has been documented to induce human autoimmune diseases in clinical use (Callahan et al., 2010Callahan M.K. Wolchok J.D. Allison J.P. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy.Semin Oncol. 2010; 37: 473-484Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar), whereas Abatacept has not so been documented so far. Abatacept is associated with an increased incidence of infections because of its immunosuppressive effects (Dubois and Cohen, 2009Dubois E.A. Cohen A.F. Abatacept.Brit J Clin Pharmacol. 2009; 68: 480-481Crossref PubMed Scopus (10) Google Scholar), but this may be acceptable to AA patients if it is shown to be efficacious for hair growth. Why is there a delay in a detailed exploration of the CTLA4 pathway(s) in human AA? A lingering bias against animal models of human disease is widespread in the medical and lay community, partly based on the not uncommon lack of treatment efficacy confirmation and/or safety issues revealed in subsequent human clinical trials. The explosion of genetic analyses studies shows that at a cellular and genetic level, there are many common regulatory pathways in human diseases and their respective animal models. When findings in a putative animal model for a specific human disease does not fulfill all the precise features of the human disease it most likely means that: (1) the original model selection was flawed, or the human disease is incompletely or incorrectly characterized, (2) the human disease is heterogenic due to genetic, ethnic, age, and gender differences in the disease susceptibility and/or variations in environmental influence; issues that cannot always be replicated with inbred animal models in a regulated environment, or (3) the methodology in the model studies or subsequent human trials was flawed leading to systematic bias (van der Worp et al., 2010van der Worp H.B. Howells D.W. Sena E.S. et al.Can animal models of disease reliably inform human studies?.PloS Med. 2010; 7: e1000245Crossref PubMed Scopus (900) Google Scholar). The challenge in developing any new therapy for human diseases involves the careful selection of a suitable preclinical model(s) to be used and well-defined human subjects to be evaluated. Although such issues cannot be ignored, the identification of a relevant animal model for a human disease can prove invaluable for studying disease mechanisms and for developing and screening new treatments. The discoveries made in humans, rats, and mice with AA over the past 20 years led to the understanding just how complex its genetics, molecular mechanisms, and its molecular pathways are (Carroll et al., 2002Carroll J. McElwee K.J. King L.E. et al.Gene array profiling and immunomodulation studies define a cell mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.J Invest Dermatol. 2002; 119: 392-402Crossref PubMed Scopus (105) Google Scholar; Subramanya et al., 2010Subramanya R.D. Coda A.B. Sinha A.A. Transcriptional profiling in alopecia areata defines immune and cell cycle control related genes within disease-specific signatures.Genomics. 2010; 96: 146-153Crossref PubMed Scopus (53) Google Scholar) in regulating its susceptibility, progression, and resolution (Sundberg et al., 2003Sundberg J.P. Boggess D. Silva K.A. et al.Major locus on mouse chromosome 17 and minor locus on chromosome 9 are linked with alopecia areata in C3H/HeJ mice.J Invest Dermatol. 2003; 120: 771-775Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, Sundberg et al., 2004Sundberg J.P. Silva K.A. Li R. et al.Adult onset alopecia areata is a complex polygenic trait in the C3H/HeJ mouse model.J Invest Dermatol. 2004; 123: 294-297Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar; Petukhova et al., 2010Petukhova L. Duvic M. Hordinsky M. et al.Genome- wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010; 466: 113-117Crossref PubMed Scopus (545) Google Scholar; John et al., 2011John K.K.-G. Brockschmidt F.F. Redler S. et al.Genetic variants in CTLA4 are strongly associated with alopecia areata.J Invest Dermatol. 2011; 131: 1169-1172Crossref PubMed Scopus (44) Google Scholar). Autoimmunity in humans and other mammals have many biological and genetic features that share many common regulatory pathways and provide valid insights (Sundberg and Schofield, 2009Sundberg J.P. Schofield P.N. One medicine, one pathology, one health concept.J Am Vet Med Assoc. 2009; 234: 1530-1531Crossref PubMed Scopus (22) Google Scholar). Though the AA models are not perfect representations of human AA, the fundamental concepts of AA in rodents and humans have proven remarkably similar thus so far. By integrating findings from multiple sources, great advances will continue to assist in developing safe and effective treatments for human and animal diseases including AA. This work was supported in part by grants from the National Alopecia Areata Foundation (JPS, KJM, LEK), the National Institutes of Health (AR43801 and AR056635 to JPS; P30AR41443 to LEK), and the Canadian Institutes of Health Research (MOP82927 to KJM)." @default.
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• W2045382802 title "Hypothesis Testing: CTLA4 Co-Stimulatory Pathways Critical in the Pathogenesis of Human and Mouse Alopecia Areata" @default.
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