The immune mechanisms that underlie the pathogenesis and/or regulation of human autoimmune diseases represent a very important but significantly understudied aspect of human disease. Our understanding of autoimmunity and its intrinsic regulation derives from extensive work in animal models that may or may not reflect essential aspects of the human disease. As a result, most of the upcoming therapeutic strategies are also based on this body of knowledge. Moreover, we have very limited mechanistic insights into how currently used immune therapeutic approaches mediate their myriad immune effects in the human disease setting. To develop better diagnostic and treatment strategies, it is critical to study human immune disease directly and to dissect the mechanisms of immune therapies as best as can be done, given the constraints of the clinical situation. This would not only provide invaluable insights, but would allow us to develop better models of these diseases incorporating under-represented aspects of the disease. With that in the mind, the principal investigator (PI) has built a career in patient-oriented research, specifically focusing on the processes that underlie immune-mediated diseases and their therapies. This K24 mid-career investigator award will provide the PI with the resources and the protected time to mentor physician-scientists at various stages of their careers in this area of research. The major focus of the PI's laboratory is the immunology of multiple sclerosis, an immune-mediated demyelinating disease of the central nervous system. The studies proposed here will apply current knowledge about the MS immune system to develop a diagnostic laboratory test for the immunologic monitoring of this disease. Other collaborative projects available for appropriate trainees include the dissection of immune dysregulation underlying hepatitis C virus infection, the pre-clinical validation of therapeutic allodepletion for minimizing graft-versus-host disease and diagnostic issues in hematologic and immunologic diseases. The PI's own division and department have large residency and fellowship programs (including both MD/PhD and MD candidates) as well as junior faculty with a particular interest in research. He is an active participant in several collaborative teams spanning multiple departments and has a track record of mentoring MSTP students, residents, fellows and junior faculty in the departments of pathology, neurology and internal medicine. The environment at UT Southwestern provides outstanding support for the development of this program, with multiple internal mechanisms of support and infrastructure already in place. This award will greatly facilitate the ability to train the next generation of scientists in this important NIAID endeavor.

Public Health Relevance

This K24 mid-career investigator award will support the investigator with the resources to pursue further research in understanding human autoimmune diseases and will provide the protected time to mentor physician-scientists at various stages of their careers in this area of research. The major focus of the PI's laboratory is the immunology of multiple sclerosis, an immune-mediated disease of the central nervous system. The studies conducted will dissect out how the immune system of MS patients is different from that of healthy individuals, with the potential of unveiling important treatment and diagnostic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
3K24AI079272-02S1
Application #
8113616
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2010-08-02
Project End
2012-07-31
Budget Start
2010-08-02
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$50,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Itani, Farah R; Sinha, Sushmita; Brate, Ashley A et al. (2017) Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen. Sci Rep 7:1519
Mohiuddin, Imran H; Pillai, Vinodh; Baughman, Ethan J et al. (2016) Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis. Clin Immunol 166-167:12-8
Sinha, Sushmita; Crawford, Michael P; Ortega, Sterling B et al. (2015) Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis. J Mult Scler (Foster City) 2:
Sinha, Sushmita; Boyden, Alexander W; Itani, Farah R et al. (2015) CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis. Front Immunol 6:619
Ortega, Sterling B; Kashi, Venkatesh P; Cunnusamy, Khrishen et al. (2015) Autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants. Neurol Neuroimmunol Neuroinflamm 2:e170
Kashi, Venkatesh P; Ortega, Sterling B; Karandikar, Nitin J (2014) Neuroantigen-specific autoregulatory CD8+ T cells inhibit autoimmune demyelination through modulation of dendritic cell function. PLoS One 9:e105763
Sinha, Sushmita; Itani, Farah R; Karandikar, Nitin J (2014) Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res 59:254-65
Cunnusamy, Khrishen; Baughman, Ethan J; Franco, Jorge et al. (2014) Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells. Clin Immunol 152:115-26
Ortega, Sterling B; Kashi, Venkatesh P; Tyler, Andrew F et al. (2013) The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis. J Immunol 191:117-26
Tyler, Andrew F; Mendoza, Jason P; Firan, Mihail et al. (2013) CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease. PLoS One 8:e66772

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