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 laboratory discovered MHC class I with contained endogenous peptides was a pathway for self-tolerance and this pathway was interrupted in diverse human and murine autoimmune diseases. In a well-established autoimmune model, the NOD mouse, the defect tracked to a proteasome defects in intracellular processing. This underlying defect additionally ablated activation of a central transcription factor, NF-kB and confers autoimmune specific phenotypes of accelerated apoptosis in response to TNF. 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, her work has shown that 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. The promise of this work allows her to move these projects forward into the clinic in a large translational project at the Massachusetts General Hospital.

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 went through Phase III trials in the form of pig neurons to humans with end-stage Parkinson's disease. Unfortunately because of fears of cross species transmissions of infectious diseases these trials were halted even when neurological function improved. This technology and patent is 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 for CD8 T cell education; interrupted education and poor lymphoid development in the autoimmune setting was discovered by Faustman as central to autoimmune diabetes as well as some other autoimmune diseases.

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 cells 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 both regeneration and rescue. The discovery that the adult pancreas could regenerate was disruptive technology that 7 years later is accepted by most as a novel and central discovery for future investigations aimed at disease reversal.

Islet Regeneration Program. In the process of developing ways to only kill autoreactive T cells, Dr Faustman discovered that the pancreas of end-stage diabetic mice could regenerate, even late in the disease process, and restore blood sugars to normal for the life of the formerly diabetic animals. The first description of this regeneration was in 2001 than this was followed in 2003 by a paper in Science describing in detail the regenerative process. Although this disruptive technology challenged the concept that islet or stem cell transplants, international efforts confirm the Faustman protocol would cure diabetes, at least in mice in a targeted manner and restore blood sugars by pancreas regeneration. The regenerative process in the mice with targeted disease removal is accomplished in full without the addition of any exogenous stem cell. The Faustman lab also identified a potent multi-lineage potential stem cell of the spleen that under select conditions contributes to the regeneration of the pancreas of recently treated NOD mice and is similarly present in human spleens from donors of all ages.

Clinical Trial to Reverse Diabetes in Long Standing Diabetics: Translation to the Clinic. Since 2003, large efforts in the Faustman laboratory are devoted to devising methods to track autoreactive T cells in human blood. Furthermore these efforts have centered on automation technology that will allow blood separations with high quality and reproducibility. These studies now allow the verification that humans with long standing diabetes still have moniotirable quantities of autorective T cells and also that these pathogenic T cells specifically die with TNF. Furthermore the TNF killing of only autoreactive T cells maps to killing only through the TNFR2 receptor. This permits the development of targeted therapeutics to kill only disease causing cells without potential side effects to the overall host. As Dr Faustman moves basic science discoveries to the clinic, the technology is feasible within academia because a cheap generic drug, BCG, which is viewed as one of the safest vaccines in the history of world is in use in a proof of principle trial at the Massachusetts General Hospital. This vaccine induces endogenous TNF and it is TNF that Faustman lab discovered kills autoreactive T cells, induces T regulatory cells and reverse even long standing murine diabetes by pancreas regeneration.

References:

Faustman DL. Immunotherapy on trial for new-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1956-8.
Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13644-9.
Lonyai A, Kodama S, Burger D, Faustman DL. Fetal Hox11 expression patterns predict defective target organs: a novel link between developmental biology and autoimmunity. Immunol Cell Biol. 2008 May-Jun;86(4):301-9.
Lonyai A, Kodama S, Burger D, Davis M, Faustman DL. The promise of Hox11+ stem cells of the spleen for treating autoimmune diseases. Horm Metab Res. 2008 Feb;40(2):137-46.
Dieguez-Acuna FJ, Gygi SP, Davis M, Faustman DL. Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans. Leukemia. 2007 Oct;21(10):2192-4.
Faustman DL. Permanent reversal of diabetes in NOD mice. Science. 2007 Jul 13;317(5835):196.
Faustman DL. Reversal of type 1 diabetes in mice. N Engl J Med. 2007 Jan 18;356(3):311-2.
Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis. 2007 Jun;66(6):812-4.
Faustman DL, Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Toth ZE, Mezey E. Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice. Science. 2006 Nov 24;314(5803):1243; author reply 1243.
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.
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.






			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 laboratory discovered MHC class I with contained endogenous peptides was a pathway for self-tolerance and this pathway was interrupted in diverse human and murine autoimmune diseases. In a well-established autoimmune model, the NOD mouse, the defect tracked to a proteasome defects in intracellular processing. This underlying defect additionally ablated activation of a central transcription factor, NF-kB and confers autoimmune specific phenotypes of accelerated apoptosis in response to TNF. 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, her work has shown that 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. The promise of this work allows her to move these projects forward into the clinic in a large translational project at the Massachusetts General Hospital. 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 went through Phase III trials in the form of pig neurons to humans with end-stage Parkinson's disease. Unfortunately because of fears of cross species transmissions of infectious diseases these trials were halted even when neurological function improved. This technology and patent is 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 for CD8 T cell education; interrupted education and poor lymphoid development in the autoimmune setting was discovered by Faustman as central to autoimmune diabetes as well as some other autoimmune diseases. 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 cells 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 both regeneration and rescue. The discovery that the adult pancreas could regenerate was disruptive technology that 7 years later is accepted by most as a novel and central discovery for future investigations aimed at disease reversal. Islet Regeneration Program. In the process of developing ways to only kill autoreactive T cells, Dr Faustman discovered that the pancreas of end-stage diabetic mice could regenerate, even late in the disease process, and restore blood sugars to normal for the life of the formerly diabetic animals. The first description of this regeneration was in 2001 than this was followed in 2003 by a paper in Science describing in detail the regenerative process. Although this disruptive technology challenged the concept that islet or stem cell transplants, international efforts confirm the Faustman protocol would cure diabetes, at least in mice in a targeted manner and restore blood sugars by pancreas regeneration. The regenerative process in the mice with targeted disease removal is accomplished in full without the addition of any exogenous stem cell. The Faustman lab also identified a potent multi-lineage potential stem cell of the spleen that under select conditions contributes to the regeneration of the pancreas of recently treated NOD mice and is similarly present in human spleens from donors of all ages. Clinical Trial to Reverse Diabetes in Long Standing Diabetics: Translation to the Clinic. Since 2003, large efforts in the Faustman laboratory are devoted to devising methods to track autoreactive T cells in human blood. Furthermore these efforts have centered on automation technology that will allow blood separations with high quality and reproducibility. These studies now allow the verification that humans with long standing diabetes still have moniotirable quantities of autorective T cells and also that these pathogenic T cells specifically die with TNF. Furthermore the TNF killing of only autoreactive T cells maps to killing only through the TNFR2 receptor. This permits the development of targeted therapeutics to kill only disease causing cells without potential side effects to the overall host. As Dr Faustman moves basic science discoveries to the clinic, the technology is feasible within academia because a cheap generic drug, BCG, which is viewed as one of the safest vaccines in the history of world is in use in a proof of principle trial at the Massachusetts General Hospital. This vaccine induces endogenous TNF and it is TNF that Faustman lab discovered kills autoreactive T cells, induces T regulatory cells and reverse even long standing murine diabetes by pancreas regeneration. References: Faustman DL. Immunotherapy on trial for new-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1956-8. Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13644-9. Lonyai A, Kodama S, Burger D, Faustman DL. Fetal Hox11 expression patterns predict defective target organs: a novel link between developmental biology and autoimmunity. Immunol Cell Biol. 2008 May-Jun;86(4):301-9. Lonyai A, Kodama S, Burger D, Davis M, Faustman DL. The promise of Hox11+ stem cells of the spleen for treating autoimmune diseases. Horm Metab Res. 2008 Feb;40(2):137-46. Dieguez-Acuna FJ, Gygi SP, Davis M, Faustman DL. Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans. Leukemia. 2007 Oct;21(10):2192-4. Faustman DL. Permanent reversal of diabetes in NOD mice. Science. 2007 Jul 13;317(5835):196. Faustman DL. Reversal of type 1 diabetes in mice. N Engl J Med. 2007 Jan 18;356(3):311-2. Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E. Reversal of Sjogren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis. 2007 Jun;66(6):812-4. Faustman DL, Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Toth ZE, Mezey E. Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice. Science. 2006 Nov 24;314(5803):1243; author reply 1243. 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. 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.