THE EFFECT OF CD48 INHIBITION IN MOUSE MEMORY T CELLS AND CELIAC DISEASE. Suzannah Bergstein

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1 THE EFFECT OF CD48 INHIBITION IN MOUSE MEMORY T CELLS AND CELIAC DISEASE Suzannah Bergstein

2 Why Study Celiac Disease? 2-3 million people in the United States diagnosed with Celiac Disease (CD) About 20 million people in the world 1 in 133 people 9 out of 10 people are unaware they have this disease no symptoms (Fasano, 2009)

Celiac Disease Gastrointestinal autoimmune disease- NOT gluten allergy Immune response triggered by gluten (found in wheat, rye, barley and oats) T cells attack the cells of the small intestine

3 Celiac Disease Gastrointestinal autoimmune disease- NOT gluten allergy Immune response triggered by gluten (found in wheat, rye, barley and oats) T cells attack the cells of the small intestine inflammation, villous atrophy, crypt hyperplasia, malabsorption Current treatment: gluten-free diet (GFD) (Lindfords et al, 2012); (Abadie et al, 2011)

4 Genetic vs. Environmental Factor Environmental Factor: Gluten Genetic Factor HLA-DQ2 and HLA-DQ8 molecules Present antigen (gluten) to T cells Jabri & Sollid, Nat Rev Immunol 2009

Memory Cells Created and activated when antigen enters body stronger immune response produced upon next encounter Two types: central memory (CM) cells

5 Memory Cells Created and activated when antigen enters body stronger immune response produced upon next encounter Two types: central memory (CM) cells and effector memory (EM) cells CM have protein CCR7 EM produce IL-4 and IFN-γ

6 The Protein CD48 Cluster of differentiation 48 Found on the surface of lymphocytes, dendretic cells, and endothelial cells It is a co-stimulatory receptor of immunity its binding with 2B4 (CD244) is responsible for co-activation of T cells ** influences CD Found on memory cells

7 Research Questions 1. How does CD48 affect memory cells? 2. Does adding CD48 antibody change the population of memory cells? 3. Will CD48 expression vary with the different types of memory cells?

5, FITC, APC, BV421and PE, respectively.

8 Methods Spleen cells taken from mouse to obtain active T cells For flow cytometry (FACS): Proteins CD4/CD8, CD62L, CD44, CCR7, and HM-48 were stained with the fluorescents PerCp-Cy5.5, FITC, APC, BV421and PE, respectively. Stainings used to identify population of CM and EM cells.

9 Methods (continued) CD4+/CD8+ CM and EM cells stimulated with CD3 antibody to keep cells active Divided into 4 categories: non-activated cells, activated cells with no treatment, activated cells with hamster IgG (hmigg) control and activated cells with CD48 antibody. hmigg control: an isotope control to which the CD48 antibody treatment could be compared Measure CD48 expression and amount of memory cells after 3 days; reactivate cells and measure again after 7 days

10 Results/Discussion CD48 expression on activated (CD3 Ab; 72hrs) CD4 + effector and central memory cells -CD48 expression is moderately and highly increased on effector and central memory cells, respectively -The HM-48 (hamster anti-cd48 Ab) binds to CD48 on the surface of the cells, and reduces the anti-cd48 detection Ab binding to the surface of CD48 (HM-48 occupies the receptor)

antibody -CD48 not was expressed (due to the CD48

11 Results/Discussion Generation of effector and central memory CD4 + T cells in presence of blocking CD48 antibody -CD48 not was expressed (due to the CD48 antibody), less activation of T cells occurred; more memory cells were present

12 Results/Discussion CD48 expression on activated (CD3 Ab re-activation; Day 7) CD4 + effector and central memory cells -CD48 expression on effector memory cells did not change, and increased on central memory cells (as compared to naïve cells.) -Increase in CD48 expression

13 Results/Discussion Generation of effector and central memory CD4 + T cells in presence of blocking CD48 antibody -The CD48 antibody treatment of these cells did not change the proportion of the central or effector memory cells.

14 Conclusions Percentage of memory cells increased under this treatment due to the fact that there were less T cells activated and present Reinforces that co-stimulation occurs No differences were observed between CD48 antibody and hmigg control treated groups in CD8+ cells; displays that control was comparable to the antibody Time has no significant impact on results (3 day vs. 7 day) Decrease in T cells may be able to eventually suppress the immune response of CD

15 Future Research Relationship between CD48 and memory cells has become clearer Could target the CD48 protein in order to prevent memory cells from recognizing and remembering gluten as a foreign antigen Decrease of T cell attack would lessen the immune response of the disease as a whole

16 Bibliography Abadie, Valerie. "Integration of Genetic and Immunological Insights into a Model of Celiac Disease Pathogenesis." Annual Review of Immunology. (2011): Print. Barera, Graziano, Riccardo Bonfanti, et al. "Occurrence of Celiac Disease After Onset of Type 1 Diabetes: A 6-Year Prospective Longitudinal Study." Pediatrics (2002): n. page. Print. Bodd, M, CY Kim, et al. "T-Cell Response to Gluten in Patients With HLA-DQ2.2 Reveals Requirement of Peptide-MHC Stability in Celiac Disease." Gastroenterology. (2011): n. page. Print. Di Sabatino, A, A Vanoli, et al. "The function of tissue transglutaminase in celiac disease." Autoimmune Review. (2012): n. page. Print. J. Delves, Peter, Seamus J. Martin, Dennis R. Burton, and Ivan M. Roitt. Essential Immunology. 11th ed. Malden, Massachusetts: Blackwell Publishing, Print. Jabri, Bana, and Ludvig M. Sollid. "Tissue-mediated control of immunopathology in coeliac disease." Tissue-Specific Immune Responses. 9. (2009): Print. Kostic, Ana, Wen Zhang, et al. "A Fully Human IL4Ra Antibody for Inhibition of IL-4/IL-13-driven Th2 Responses in Allergic Disease." Clinical Immunology (2010): n. page. Print. Lindfors, K, T Rauhavirta, et al. "In vitro models for gluten toxicity: relevance for celiac disease pathogenesis and development of novel treatment options." Experimental Biology and Medicine. (2012): 1-7. Print. Ludvigsson, Jonas F., Johnny Ludvigsson, et al. "Celiac Disease and Risk of Subsequent Type 1 Diabetes." Diabetes Care (2006): Print. Papista, C, and V Gerakopoulos. "Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics." Lab Invest. (2012): n. page. Print. Saez, LR, DF Alvarez, et al. "Refractory iron-deficiency anemia and gluten intolerance- Response to gluten-free diet." Rev Esp Enferm Dig (2011): Print. Sperandeo, MP, A Tosco, et al. "Potential celiac patients: a model of celiac disease pathogenesis." PLoS One. (2011): n. page. Print. Tanaka, Toshio, Masashi Narazaki, et al. "Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases." Federation of European Biochemical Societies. (2011): n. page. Print.

Coeliac Disease Bible Class Questions and Answers

Coeliac Disease Bible Class Questions and Answers Jan Hendrik Niess What is the definition of coeliac disease? Coeliac disease is an immune reaction to gluten (wheat, barely, rye) in an genetic predisposed