BADERC-Denise Faustman

Denise Faustman, M.D.,Ph.D.

Type I diabetes: autoimmunity and islet regeneration

Dr. Faustman’s current research program investigates human and murine Type I diabetes. She specifically investigates immunologic and genetic derangements as they relate to phenotypes of disease expression. In 1991, her laboartory discovered MHC class I with contained endogenous peptides was a pathway for self tolerance and was interrupted in diverse human and murine autoimmune diseases. In a well-established autoimmune model, the NOD mouse, the defect tracks to a proteasome defect in intracellular processing. This underlying defect additionally ablates activation of a central transcription factor, NF-kB and confers autoimmune specific phenotypes of accelerated apoptosis in response to TNF-a. New therapies are being developed based on these underlying defects including interventions that can effectively halt existing disease. In the case of type 1 diabetes, some animal models have the ability to regenerate the existing islet cells in the pancreas and thus confer an effective permanent disease reversal without the introduction of stem cells.

Cellular Transplantation Program. Dr. Faustman created the MGH research program to identify the target molecules on donor tissues which trigger T cell recognition and cause transplant rejection. Achievements include: the successful application of designer donor tissues (donor antigen modification) to transplant foreign cells without immunosuppression into small and large animal models; the first application of this technology to diverse tissues (e.g. liver, neurons and muscle); elucidation of basic mechanisms of active tolerance which sustains graft acceptance as it relates to donor antigen modifications; translation of the technology to human clinical trials. This xenograft technology in 1995 represented the first FDA approval for cross species (pig to human) clinical trials in the US. This technology has been successfully commercialized and is in Phase I-II clinical trials for five human diseases. This technology and patent is the central for expansion of animal cloning methods to prevent host recognition by modification of cells/animals prior to transplantation.

Human Islet Cell Transplantation Program. Techniques for islet isolation and immunological manipulation were translated to clinical practice with the creation of the first islet cell transplantation program for diabetes in New England in cooperation with Dr. David Nathan. The Immunobiology Laboratory under Dr. Faustman’s designed and implementation of an automated process to transplant islets into humans, a process originally developed from research involving her thesis work at Washington University. Critical collaborations with regional and national organ banks were established to ensure an adequate pancreas supply.

Basic Science Programs. The Immunobiology Laboratory under Dr. Faustman’s direction investigates mechanisms used by the immune system to broaden and diversify the immune response. Traditionally, T cell education has been viewed as composed of T cell receptor gene rearrangement combined with allelic variability of the MHC class I/II gene products. Projects in Dr. Faustman’s laboratory have uncovered the Tap and Lmp genes as contributors to variable peptide selection; interrupted education and poor lymphoid development in the autoimmune setting.

Autoimmune Programs. Dr. Faustman’s 15 year research program on autoimmunity has been a protein/cell based approach utilizing comparisons between affected and unaffected identical human twins or disease disparate inbred NOD mice with autoimmune diabetes. This has led to the discovery of an overabundance of naïve T cells, defects in antigen presenting cells, defects in MHC class I presentation of self-peptides, altered NF-kB activation/regulation and hampered resistance to cytokine induced apoptosis. These protein processing defects are specific to the diseased cell of the affected cohort regardless of genotype. These phenotypes have successfully been used as therapies to permanently reverse disease in spontaneously diabetic mice. The long-term follow-up of these mice reveals restored normoglycemia is due to the restoration of pancreatic insulin secretion with islet reappearance due to presumed regeneration or rescue.

References:

1. Faustman D, Coe C. Prevention of xenograft rejection by masking donor HLA class I antigens. Science. 1991;252:1700-2.

2. Faustman D, Li X, Lin H.Y, Fu Y, Eisenbarth G, Avruch J, Guo J. Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science. 1991;254:1756-61.

3. Faustman D, Li X, Lin HY, Huang R, Guo J. Expression of intra-MHC transporter (HAM) genes and class I antigens in diabetes - susceptible NOD mice. Science 1992;256:1826-31.

4. Fu Y, Nathan DM, Li F, Li X, Faustman DL. Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity. J Clin Invest. 1993;91:2301-7.

5. Li F, Guo J, Fu Y, Yan G, Faustman D. Abnormal class I assembly and peptide presentation in the nonobese diabetic mouse. Proc Natl Acad Sci USA. 1994;91:11128-32.

6. Hayashi, T. Faustman, D. NOD mice are defective in proteasome production and activation of NF-kB. Molec. Cell Biol. 1999; 19:8646-8659.

7. Hayashi, T. Faustman, D. Essential role of human leukocyte antigen-encoded proteasome subunits in NF-kB activation and prevention of TNF-a induced apoptosis. J. Biol. Chem. 2000; 275:5238-5247.

8. Hayashi T, Kodama S, Faustman D. Reply to 'LMP2 expression proteasome activity in NOD mice. Nature Med 2000; 6:1065-1066.

9. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous ß-cell function. J Clin Invest. 2001; 108:63-72.

10. Yan G, Shi L, Penfornis A, Faustman DL. Impaired processing and presentation by MHC class II proteins in human diabetic cells. J Immunol. 2003;170:620-7.

11. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science. 2003;302:1223-7.






			Denise Faustman, M.D.,Ph.D. Type I diabetes: autoimmunity and islet regeneration Dr. Faustman’s current research program investigates human and murine Type I diabetes. She specifically investigates immunologic and genetic derangements as they relate to phenotypes of disease expression. In 1991, her laboartory discovered MHC class I with contained endogenous peptides was a pathway for self tolerance and was interrupted in diverse human and murine autoimmune diseases. In a well-established autoimmune model, the NOD mouse, the defect tracks to a proteasome defect in intracellular processing. This underlying defect additionally ablates activation of a central transcription factor, NF-kB and confers autoimmune specific phenotypes of accelerated apoptosis in response to TNF-a. New therapies are being developed based on these underlying defects including interventions that can effectively halt existing disease. In the case of type 1 diabetes, some animal models have the ability to regenerate the existing islet cells in the pancreas and thus confer an effective permanent disease reversal without the introduction of stem cells. Cellular Transplantation Program. Dr. Faustman created the MGH research program to identify the target molecules on donor tissues which trigger T cell recognition and cause transplant rejection. Achievements include: the successful application of designer donor tissues (donor antigen modification) to transplant foreign cells without immunosuppression into small and large animal models; the first application of this technology to diverse tissues (e.g. liver, neurons and muscle); elucidation of basic mechanisms of active tolerance which sustains graft acceptance as it relates to donor antigen modifications; translation of the technology to human clinical trials. This xenograft technology in 1995 represented the first FDA approval for cross species (pig to human) clinical trials in the US. This technology has been successfully commercialized and is in Phase I-II clinical trials for five human diseases. This technology and patent is the central for expansion of animal cloning methods to prevent host recognition by modification of cells/animals prior to transplantation. Human Islet Cell Transplantation Program. Techniques for islet isolation and immunological manipulation were translated to clinical practice with the creation of the first islet cell transplantation program for diabetes in New England in cooperation with Dr. David Nathan. The Immunobiology Laboratory under Dr. Faustman’s designed and implementation of an automated process to transplant islets into humans, a process originally developed from research involving her thesis work at Washington University. Critical collaborations with regional and national organ banks were established to ensure an adequate pancreas supply. Basic Science Programs. The Immunobiology Laboratory under Dr. Faustman’s direction investigates mechanisms used by the immune system to broaden and diversify the immune response. Traditionally, T cell education has been viewed as composed of T cell receptor gene rearrangement combined with allelic variability of the MHC class I/II gene products. Projects in Dr. Faustman’s laboratory have uncovered the Tap and Lmp genes as contributors to variable peptide selection; interrupted education and poor lymphoid development in the autoimmune setting. Autoimmune Programs. Dr. Faustman’s 15 year research program on autoimmunity has been a protein/cell based approach utilizing comparisons between affected and unaffected identical human twins or disease disparate inbred NOD mice with autoimmune diabetes. This has led to the discovery of an overabundance of naïve T cells, defects in antigen presenting cells, defects in MHC class I presentation of self-peptides, altered NF-kB activation/regulation and hampered resistance to cytokine induced apoptosis. These protein processing defects are specific to the diseased cell of the affected cohort regardless of genotype. These phenotypes have successfully been used as therapies to permanently reverse disease in spontaneously diabetic mice. The long-term follow-up of these mice reveals restored normoglycemia is due to the restoration of pancreatic insulin secretion with islet reappearance due to presumed regeneration or rescue. References: 1. Faustman D, Coe C. Prevention of xenograft rejection by masking donor HLA class I antigens. Science. 1991;252:1700-2. 2. Faustman D, Li X, Lin H.Y, Fu Y, Eisenbarth G, Avruch J, Guo J. Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. Science. 1991;254:1756-61. 3. Faustman D, Li X, Lin HY, Huang R, Guo J. Expression of intra-MHC transporter (HAM) genes and class I antigens in diabetes - susceptible NOD mice. Science 1992;256:1826-31. 4. Fu Y, Nathan DM, Li F, Li X, Faustman DL. Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity. J Clin Invest. 1993;91:2301-7. 5. Li F, Guo J, Fu Y, Yan G, Faustman D. Abnormal class I assembly and peptide presentation in the nonobese diabetic mouse. Proc Natl Acad Sci USA. 1994;91:11128-32. 6. Hayashi, T. Faustman, D. NOD mice are defective in proteasome production and activation of NF-kB. Molec. Cell Biol. 1999; 19:8646-8659. 7. Hayashi, T. Faustman, D. Essential role of human leukocyte antigen-encoded proteasome subunits in NF-kB activation and prevention of TNF-a induced apoptosis. J. Biol. Chem. 2000; 275:5238-5247. 8. Hayashi T, Kodama S, Faustman D. Reply to 'LMP2 expression proteasome activity in NOD mice. Nature Med 2000; 6:1065-1066. 9. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous ß-cell function. J Clin Invest. 2001; 108:63-72. 10. Yan G, Shi L, Penfornis A, Faustman DL. Impaired processing and presentation by MHC class II proteins in human diabetic cells. J Immunol. 2003;170:620-7. 11. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science. 2003;302:1223-7.