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. Two major projects are currently ongoing:
- 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.
1. Okubo Y, Mera T, Wang L, Faustman DL. Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci Rep. 2013;3:3153. doi: 10.1038/srep03153. PMID: 24193319 [PubMed – in process]
2. Faustman DL, Wang L, Okubo Y, Burger D, Ban L, Man G, Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan DM. Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes.vPLoS One. 2012;7(8):e41756. doi: 10.1371/journal.pone.0041756.PMID: 22905105 [PubMed – indexed for MEDLINE]
3. Limei Wang, Nicholas Fraser Lovejoy, Denise L. Faustman. Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay. Diabetes Care. 2012 March; 35(3): 465–470. PMCID: PMC3322715.
4. Francisco Dieguez-Acuña, Shohta Kodama, Yoshiaki Okubo, Ana Cristina Paz, Steven P Gygi, Denise L Faustman. Proteomics identifies multipotent and low oncogenic risk stem cells of the spleen. Int J Biochem Cell Biol. 2010; 42(10): 1651–1660. PMCID: PMC2891339.
5. 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;105(36):13644-9. PMCID: PMC2533243
6. 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.
7. Faustman DL. Permanent reversal of diabetes in NOD mice. Science. 2007 Jul 13;317(5835):196.
8. 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.
9. 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.
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. 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.