Matthew B. Grisham, Ph.D.
Professor and Chair
Mucosal immunology; lymphocyte trafficking; immune regulation; pathogenetic mechanisms responsible for induction and regulation of chronic gut inflammation.
Role of Lymphocyte Function-Associated Antigen-1 (LFA-1) in the Induction of Chronic Gut Inflammation
It is well-known that CD4+ T-cells play an important role in the pathogenesis of the inflammatory bowel diseases (IBD; Crohn’s disease and ulcerative colitis). The molecular determinants responsible for homing of naïve and disease-producing effector T-cells to the gut-draining mesenteric lymph nodes (MLNs) and intestine where they initiate and perpetuate chronic gut inflammation have not been well characterized. This project utilizes variety of genetic, molecular, immunological and surgical approaches to test the hypothesis that T-cell-associated LFA-1 is required for naïve T-cell migration to and/or activation within the MLNs to produce colitogenic effector cells. Furthermore, we are evaluating the importance of LFA-1 in promoting the recruitment of disease-producing effector T-cells to the colon where these lymphocytes initiate chronic colitis.
Suppression of Chronic Intestinal Inflammation by ex vivo-Generated Regulatory T cells
Currently, there are only a handful of medical treatments available for treating patients with IBD. Thus, there is a clear need for the development of additional and more potent therapeutic agents to treat these devastating diseases. A new and exciting cell-based therapy that is being investigated is focused on a subset of CD4+ T cells expressing the transcription factor Foxp3. These naturally-occurring regulatory T-cells (termed nTregs) have been shown to suppress the development of the chronic inflammation that arises in different animal models of diabetes, multiple sclerosis, graft vs. host disease, arthritis and IBD. A major limitation in understanding how nTregs may be used to treat patients with IBD or other autoimmune diseases is the relative paucity of these regulatory cells as they constitute <10% of the peripheral CD4+ T-cell population in mice and only 1-2% of CD4+ T-cells in humans. In an attempt to overcome this significant challenge, we have recently developed an ex vivo method to convert large numbers of conventional CD4+ T-cells to Foxp3-expressing Tregs (termed induced Tregs or iTregs). We are currently evaluating the therapeutic efficacy of our ex vivo-generated iTregs in different mouse models of IBD.
Regulation of Chronic Gut Inflammation by Bone Marrow-Derived Mesenchymal Stem Cells
Another novel and potentially effective cell-based therapy that has generated a great deal of interest in the experimental and clinical communities is based upon the use ofbone marrow-derived mesenchymal stem cells (MSCs). Because these progenitor cells have been shown to be “immune privileged”, human MSCs successfully engraft in recipient mice or rats where they suppress the inflammatory tissue injury observed in animal models of autoimmune encephalomyelitis, allograft rejection, collagen-induced arthritis and graft vs. host disease. Because no attempt has been made to evaluate the therapeutic efficacy of these immune-modifying progenitor cells in animal models of chronic intestinal inflammation we are systematically evaluating the immune suppressive activity of ex vivo- generated, bone marrow-derived human MSCs in a well-characterized mouse model of chronic colonic inflammation.
Research Articles (selected from 280)
- Ostanin,D.V., Kurmaeva,E., Furr,K., Bao,R., Hoffman,J., Berney,S., and Grisham,M.B. 2012. Acquisition of antigen-presenting functions by neutrophils isolated from mice with chronic colitis. J. Immunol. 188:1491-1502.
- Koboziev,I., Karlsson,F., Ostanin,D.V., Gray,L., Davidson,M., Zhang,S., and Grisham,M.B. 2012. Role of LFA-1 in the activation and trafficking of T cells: Implications in the induction of chronic colitis. Inflamm. Bowel. Dis. (In press).
- Kalyanaraman,B., Darley-Usmar,V., Davies,K.J., Dennery,P.A., Forman,H.J., Grisham,M.B., Mann,G.E., Moore,K., Roberts,L.J., and Ischiropoulos,H. 2012. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic. Biol. Med. 52:1-6.
- Fang,K., Zhang,S., Glawe,J., Grisham,M.B., and Kevil,C.G. 2012. Temporal genome expression profile analysis during t-cell-mediated colitis: Identification of novel targets and pathways. Inflamm. Bowel. Dis. 18:1411-23.
- Koboziev,I., Karlsson,F., Zhang,S., and Grisham,M.B. 2011. Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies. Inflamm. Bowel. Dis. 17:1229-1245.
- Karlsson,F., Robinson-Jackson,S.A., Gray,L., Zhang,S., and Grisham,M.B. 2011. Ex vivo generation of regulatory T cells: characterization and therapeutic evaluation in a model of chronic colitis. Methods Mol. Biol. 677:47-61.
- Hines,I.N., and Grisham,M.B. 2011. Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury. J. Clin. Biochem. Nutr. 48:50-56.
- Harris,N.R., Carter,P.R., Yadav,A.S., Watts,M.N., Zhang,S., Kosloski-Davidson,M., and Grisham,M.B. 2011. Relationship between inflammation and tissue hypoxia in a mouse model of chronic colitis. Inflamm. Bowel. Dis. 17:742-746.
- Takebayashi,K., Koboziev,I., Ostanin,D.V., Gray,L., Karlsson,F., Robinson-Jackson,S.A., Kosloski- Davidson,M., Dooley,A.B., Zhang,S., and Grisham,M.B. 2011. Role of the gut-associated and secondary lymphoid tissue in the induction of chronic colitis. Inflamm. Bowel. Dis. 17:268-278.
- Ostanin,D.V., Brown,C.M., Gray,L., Bharwani,S., and Grisham,M.B. 2010. Evaluation of the immunoregulatory activity of intraepithelial lymphocytes in a mouse model of chronic intestinal inflammation. Int. Immunol. 22:927-939.
- Abe,Y., Urakami,H., Ostanin,D., Zibari,G., Hayashida,T., Kitagawa,Y., and Grisham,M.B. 2009. Induction of Foxp3-expressing regulatory T-cells by donor blood transfusion is required for tolerance to rat liver allografts. PLoS. One. 4:1-9.
- Harris,N.R., Whatley,J.R., Carter,P.R., Morgan,G.A., and Grisham,M.B. 2009. Altered microvascular hemodynamics during the induction and perpetuation of chronic gut inflammation. Am. J. Physiol Gastrointest. Liver Physiol 296:G750-G754.
- Ostanin,D.V., Bao,J., Koboziev,I., Gray,L., Robinson-Jackson,S.A., Kosloski-Davidson,M., Price,V.H., and Grisham,M.B. 2009. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am. J. Physiol Gastrointest. Liver Physiol 296:G135-G146.
- Chidlow,J.H., Jr., Shukla,D., Grisham,M.B., and Kevil,C.G. 2007. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am. J. Physiol Gastrointest. Liver Physiol 293:G5-G18.
- Ostanin,D.V., Furr,K.L., Pavlick,K.P., Gray,L., Kevil,C.G., Shukla,D., D'Souza,D., Hoffman,J.M., and Grisham,M.B. 2007. T cell-associated CD18 but not CD62L, ICAM-1, or PSGL-1 is required for the induction of chronic colitis. Am. J. Physiol Gastrointest. Liver Physiol 292:G1706-G1714.
- Vowinkel,T., Anthoni,C., Wood,K.C., Stokes,K.Y., Russell,J., Gray,L., Bharwani,S., Senninger,N., Alexander,J.S., Krieglstein,C.F. et al 2007. CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon. Gastroenterology 132:955-965.
- Chidlow,J.H., Jr., Langston,W., Greer,J.J., Ostanin,D., Abdelbaqi,M., Houghton,J., Senthilkumar,A., Shukla,D., Mazar,A.P., Grisham,M.B. et al 2006. Differential angiogenic regulation of experimental colitis. Am. J. Pathol. 169:2014-2030.
- Pavlick,K.P., Ostanin,D.V., Furr,K.L., Laroux,F.S., Brown,C.M., Gray,L., Kevil,C.G., and Grisham,M.B. 2006. Role of T-cell-associated lymphocyte function-associated antigen-1 in the pathogenesis of experimental colitis. Int. Immunol. 18:389-398.
- Ostanin,D.V., Pavlick,K.P., Bharwani,S., D'Souza,D., Furr,K.L., Brown,C.M., and Grisham,M.B. 2006. T cell-induced inflammation of the small and large intestine in immunodeficient mice. Am. J. Physiol Gastrointest. Liver Physiol 290:G109-G119.
Dr. Grisham occupies 2,400 sq. ft. of contiguous laboratory space located on the 5th floor of the School of Medicine. This multifunctional laboratory contains a variety of state-of-the-art molecular, cellular and immunological instrumentation and equipment as well as three separate rooms for animal procedures, cell culture and microscopy.
In addition to this lab space and equipment, Dr. Grisham’s staff and students have unlimited access to the new state-of-the-art Image Analysis Core Facility. The University is one of only three institutions in Texas to have this type of capability. The new 1,200-square-foot facility will house more than $2 million of laboratory equipment. The most powerful instrument in the Core Facility is a Nikon TiE confocal microscope equipped with an option known as N-STORM (Nikon Stochastic Optical Resolution Microscopy).
Dr. Grisham’s staff and students also have access to the Flow Cytometry suite that is operated by the Cancer Center in the School of Medicine. This state-of-the-art facility has a BD LSR II flow cytometer and a FACSAria cell sorter. The LSR II is capable of analyzing 16 simultaneous colors. It should be noted that a new multi- purpose Cell and Molecular Core will be available to all students and faculty at the Health Sciences Center in early 2013.