BADERC- Howard Weiner

Howard Weiner, M.D.

Oral Autoantigens for the Treatment of Autoimmunity

Our laboratory has a long term interest in the modulation of autoimmune diseases by oral administration of autoantigens. One of the models we have studied and are in the process of studying is the NOD model of diabetes. We have found that orally administered insulin can suppress or delay the onset of diabetes in these animals. We have also shown that the mechanism of action related to the generation of Th2 or Th3 type regulatory cells which suppress inflammation in the pancreatic islets. We continue our studies of animal models, trying to identify the effect of oral insulin in neonatal diabetes and ways in which to enhance the effect of the mucosally administered antigens. We have support for this work from the Juvenile Diabetes Association

References:

1. Maron, R, Melican, NS, and Weiner, HL (1999). Regulatory Th2 type T cell lines against insulin and GAD peptides derived from orally- and nasally- treated NOD mice suppress diabetes. Journal of Autoimmunity 12, 251-258.

2. Liu, L, Kuchroo, VK, and Weiner, HL (1999). B7.2 (CD86) but not B7.1 (CD80) costimulation is required for the induction of low dose oral tolerance. J Immunol 163, 2284-2290.

3. Weiner, HL, Lemere, CA, Maron, R, Spooner, ET, Grenfell, TJ, Mori, C, Issazadeh, S, Hancock, WW, and Selkoe, DJ (2000). Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol 48, 567-79.

4. Slavin, AJ, Maron, R, and Weiner, HL (2001). Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes. Int Immunol 13, 825-33.

5. Zhang, X, Izikson, L, Liu, L, and Weiner, HL (2001). Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J Immunol 167, 4245-53.

6. Maron, R, Slavin, AJ, Hoffmann, E, Komagata, Y, and Weiner, HL (2002). Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. Int Immunol 14, 131-8.

7. Soos, JM, Stuve, O, Youssef, S, Bravo, M, Johnson, HM, Weiner, HL, and Zamvil, SS (2002). Cutting edge: oral type I IFN-tau promotes a Th2 bias and enhances suppression of autoimmune encephalomyelitis by oral glatiramer acetate. J Immunol 169, 2231-5.

8. Maron, R, Sukhova, G, Faria, AM, Hoffmann, E, Mach, F, Libby, P, and Weiner, HL (2002). Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 106, 1708-15.

9. Gonnella PA, Kodali D, Weiner HL. Induction of low dose oral tolerance in monocyte chemoattractant protein-1- and CCR2-deficient mice. J Immunol. 2003;170:2316-22.

10. Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism.J Immunol. 2003 ;170:2516-22.

11. Wu HY, Weiner HL. Oral Tolerance. Immunol Res. 2003;28(3):265-84.

12. Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells.Int Immunol. 2004;16:249-56.

13. Karni A, Balashov K, Hancock WW, Bharanidharan P, Abraham M, Khoury SJ, Weiner HL. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol. 2004;146:189-98.






			Howard Weiner, M.D. Oral Autoantigens for the Treatment of Autoimmunity Our laboratory has a long term interest in the modulation of autoimmune diseases by oral administration of autoantigens. One of the models we have studied and are in the process of studying is the NOD model of diabetes. We have found that orally administered insulin can suppress or delay the onset of diabetes in these animals. We have also shown that the mechanism of action related to the generation of Th2 or Th3 type regulatory cells which suppress inflammation in the pancreatic islets. We continue our studies of animal models, trying to identify the effect of oral insulin in neonatal diabetes and ways in which to enhance the effect of the mucosally administered antigens. We have support for this work from the Juvenile Diabetes Association References: 1. Maron, R, Melican, NS, and Weiner, HL (1999). Regulatory Th2 type T cell lines against insulin and GAD peptides derived from orally- and nasally- treated NOD mice suppress diabetes. Journal of Autoimmunity 12, 251-258. 2. Liu, L, Kuchroo, VK, and Weiner, HL (1999). B7.2 (CD86) but not B7.1 (CD80) costimulation is required for the induction of low dose oral tolerance. J Immunol 163, 2284-2290. 3. Weiner, HL, Lemere, CA, Maron, R, Spooner, ET, Grenfell, TJ, Mori, C, Issazadeh, S, Hancock, WW, and Selkoe, DJ (2000). Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol 48, 567-79. 4. Slavin, AJ, Maron, R, and Weiner, HL (2001). Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes. Int Immunol 13, 825-33. 5. Zhang, X, Izikson, L, Liu, L, and Weiner, HL (2001). Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J Immunol 167, 4245-53. 6. Maron, R, Slavin, AJ, Hoffmann, E, Komagata, Y, and Weiner, HL (2002). Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. Int Immunol 14, 131-8. 7. Soos, JM, Stuve, O, Youssef, S, Bravo, M, Johnson, HM, Weiner, HL, and Zamvil, SS (2002). Cutting edge: oral type I IFN-tau promotes a Th2 bias and enhances suppression of autoimmune encephalomyelitis by oral glatiramer acetate. J Immunol 169, 2231-5. 8. Maron, R, Sukhova, G, Faria, AM, Hoffmann, E, Mach, F, Libby, P, and Weiner, HL (2002). Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 106, 1708-15. 9. Gonnella PA, Kodali D, Weiner HL. Induction of low dose oral tolerance in monocyte chemoattractant protein-1- and CCR2-deficient mice. J Immunol. 2003;170:2316-22. 10. Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism.J Immunol. 2003 ;170:2516-22. 11. Wu HY, Weiner HL. Oral Tolerance. Immunol Res. 2003;28(3):265-84. 12. Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells.Int Immunol. 2004;16:249-56. 13. Karni A, Balashov K, Hancock WW, Bharanidharan P, Abraham M, Khoury SJ, Weiner HL. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol. 2004;146:189-98.