Jon D. Piganelli, Ph.D.
Campus: 4401 Penn Avenue
Office: 6125 Research Center
Lab: Rangos Research Center
Pittsburgh, PA 15224
- B.S. - Colorado State University
- Ph.D. - Oregon State University
- Postdoc - University of Colorado Health Sciences Center / Barbara Davis Center for Childhood Diabetes
- Associate Professor, Department of Surgery
- Department Of Immunology
- Department of Pathology
Targeting Redox-Dependent T cell activation and Metabolism in the Autoimmune Response to Prevent Type 1 Diabetes
My group has been involved in studying immunology and autoimmunity; more specifically type 1 diabetes (T1D). My work primarily focuses on the role of oxidative stress and free radical generation and how it leads to secondary inflammation, since the majority of pathological conditions have an inflammatory component. Also these redox reactions are critical for synergizing the innate and adaptive immune response, and exploitation of these reactions can modulate immune function in a variety of diseases. I have studied these interaction in both human islets isolated from cadaveric donors as well as in animal models of T1D like the NOD mouse. Furthermore, my group’s work has demonstrated that modulation of redox dependent signaling can have positive effects on controlling aberrant immune responses as well as the protection and preservation of organs and tissue for transplantation. Our group has utilized small molecule manganese porphyrin oxidoreductases (MnP) as a potential immunoregulatory therapy for type 1 diabetes. MnPs have previously been shown to modulate diabetogenic immune responses through decreases in proinflammatory cytokine production from antigen-presenting cells and T cells and to reduce diabetes onset in nonobese diabetic mice. We have also demonstrated that MnP treatment can act beyond our previous reports of controlling inflammatory mediators. MnP treatment marked effects on regulating redox-dependent cell surface receptors responsible for full T cell activation. Furthermore we have demonstrated that modulating redox balance also effects metabolic switch of T cells during activation by impeding the switch of T cells from oxidative phosphorylation to glycolysis, a critical step for full T cell activation. This effect has an impact on activated T cell transition from activation to effector function. These alterations likely occur through the stabilization of oxidative phosphorylation, thus impeding glycolysis. MnP treatment promotes metabolic quiescence, impeding diabetogenic autoimmune responses by restricting the metabolic pathways for energy production and affecting anabolic processes necessary for cell proliferation. We are very excited about these findings as they may allow of an innovative way of controlling aberrant immune response in a selective way.
Modulating islet ER-Stress to Reduce Self-Reactive T cell Recognition.
The lab is also interested in studying how environmental triggers affect the progression of autoimmune disease like type 1 diabetes. We have begun to dissect the role of endoplasmic reticulum stress (ER-stress) in beta cells as a result of normal protein production and how this ER-stress may lead to an aberrant immune response in those individuals that are genetically predisposed to autoimmunity. Essentially, it appears that the normal physiological response to ER-stress results in the recognition of ER-stress associated proteins by the immune system as being foreign.
Beta Cell and Macrophage Cross Talk in the Face of Autoimmunity.
We are also interested in studying the process of T cell-mediated destruction of pancreatic beta cells and how it results in activation of macrophages to a cytotoxic phenotype (M1) leading to inflammatory beta cell destruction driven in part by self-reactive CD4+ T cells. It known that endogenous beta cell growth can occur if the inflammatory immune attack is tempered. In fact as seen in wound healing a more controlled inflammatory response appears to be necessary to induce the regenerative process, characterized by a transition of macrophage phenotypes from inflammatory (M1) to anti-inflammatory (M2) to initiate the repair and normal regenerative process. Macrophages from the autoimmune NOD mouse however, are known to have a number of maturation defects. Therefore, we hypothesize that upon β cell destruction these defective macrophages fail to transition from the M1 to M2 phenotype, rendering the β cells unable to initiate the repair program. We are actively pursuing this hypothesis to better determine if stopping the immune onslaught is in and of itself enough, or do we also need to foster better ways to maintain b cell repair and regeneration.
Negative Vaccination for Prevention of Type 1 Diabetes
Our efforts focus on the critical question: “Can we vaccinate against type 1 diabetes (T1D) by prophylactically re-educating the immune system through antigen specific “negative vaccination”, coupled with direct islet β cell cytoprotection to prevent type 1 diabetes?” This work addresses the current gap in treatment approaches by using islet b cell proteins immunizing antigens in conjunction with a small molecule manganese porphyrin (MnP), which we have reported leads to presentation of autoantigens in a tolerogenic fashion as well as being highly β cell cytoprotective. By directly protecting β cells, while regulating the aberrant immune response, we provide a dual approach to induce self-tolerance and maintain residual β cell mass.
The ability to predict non-progressors to progressors, prior to type 1 diabetes disease onset, provides us with the opportunity to be proactive and subvert the self-reactive immune response toward β cells by vaccinating with β cell antigens under suboptimal conditions or “negative vaccination” to promote antigen-specific tolerance induction. Utilizing short-term therapy providing durable self-tolerance in the absence of global immunosuppression, will result in blunted disease progression and maintenance of β cell mass.
- Criscimanna A, Coudriet GM, Gittes GK, Piganelli JD, Esni F. .Activated Macrophages Create Lineage-specific Microenvironments for Pancreatic Acinar- and β-cell Regeneration in Mice.Gastroenterology. 2014 Aug 13 [Epub ahead of print PMID:25128759
- Delmastro-Greenwood MM, Votyakova T, Goetzman E, Marre ML, Previte DM, Tovmasyan A, Batinic-Haberle I, Trucco M, Piganelli JD. Mn Porphyrin Regulation Of Aerobic Glycolysis: Implications On The Activation Of Diabetogenic Immune Cells. Antioxid Redox Signal. 2013 Jul 5. [Epub ahead of print] PMID:23682840
- Delmastro-Greenwood MM, Tse HM, Piganelli JD Effects of Metalloporphyrins on Reducing Inflammation and Autoimmunity. Antioxid Redox Signal. 2013 Mar 9. [Epub ahead of print] PMID: 23472672
- Delmastro-Greenwood, M.M. and Piganelli JD. Changing the energy of an immune response. Am J Clin Exp Immunol 2013;2(1): 30-54.PMID: 23885324
- Yagi H, Fukumitsu K, Fukuda K, Kitago M, Shinoda M, Obara H, Itano O, Kawachi S, Tanabe M, Coudriet GM, Piganelli JD, Gilbert TW, Soto-Gutierrez A, Kitagawa Y. Human-Scale Whole-Organ Bioengineering for Liver Transplantation: a Regenerative Medicine Approach. Cell Transplant 2013;22(2):231-42.PMID: 22943797
- Sklavos, M M, Coudriet, G. M., Delmastro, M. M., Bertera, S., Coneybeer, J.T., He J., Trucco, M., Piganelli, J.D. Administration of a negative vaccination induces hypo-responsiveness to islet allografts. Cell Transplantation 2013;22(7):1147-55. PMID: 23031818
- Delmastro MM, Styche AJ, Trucco, MM, Workman, CJ, Vignali, DAA and Piganelli, JD. Modulation of redox balance leaves murine diabetogenic TH1 T cells ‘LAG-3-ing’ behind. Jul;61(7):1760-8 Diabetes 2012. PMID: 22586584
- Barbara M. Schulte, Kjerstin H.W. Lanke, Jon D. Piganelli, Esther D. Kers-Rebel, Rita Bottino, Massimo Trucco, Richard J.F. Huijbens, Timothy R.D.J. Radstake, Marten.A. Engelse, Eelco J. P. de Koning, Jochem M.D. Galama, Gosse J. Adema and Frank J.M. van Kuppeveld. Cytokine and chemokine production by human pancreatic islets upon enterovirus infection. Diabetes 2012 Aug. 61 (8)2030-2036.PMID: 22596052
- Manni ML, Epperly MW, Han W, Blackwell TS, Duncan SR, Piganelli JD, Oury TD.Leukocyte-derived Extracellular Superoxide Dismutase does not contribute to Airspace EC-SOD after Interstitial Pulmonary Injury.Am J Physiol Lung Cell Mol Physiol. Jan;302,(1):L160-6 2012 PMID: 22003088
- Lin MS, Tse HM, Delmastro MM, Bertera S, Wong CT, Lakomy R, He J, Sklavos MM, Coudriet GM, Pietropaolo M, Trucco MM, Piganelli JD. A multivalent vaccine for type 1 diabetes skews T cell subsets to Th2 phenotype in NOD mice. Immunol Res. 2011 Aug;50(2-3):213-20. PMID: 21717080
- Thayer TC, Delano M, Liu C, Chen J, Padgett LE, Tse HM, Annamali M, Piganelli JD, Moldawer LL, Mathews CE. Superoxide Production by Macrophages and T Cells Is Critical for the Induction of Autoreactivity and Type 1 Diabetes. 2011 Diabetes. Aug; 60(8):2144-51. PMID: 21715554
- Sheng H, Spasojevic I, Tse HM, Jung JY, Hong J, Zhang Z, Piganelli JD, Batinic-Haberle I, Warner DS. Neuroprotective Efficacy From A Lipophilic Redox-Modulating MnPorphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage. J Pharmacol Exp Ther. 2011 Sep;338(3):906-16. PMID: 21652782
- Delmastro MM, Piganelli JD. Oxidative stress and redox modulation potential in type 1 diabetes. Clin Dev Immunol. 2011;2011:593863. Epub 2011 May 18. PMID: 21647409
- Manni ML, Tomai LP, Norris CA, Thomas LM, Kelley EE, Salter RD, Crapo JD, Chang LY, Watkins SC, Piganelli JD, Oury TD. Extracellular superoxide dismutase in macrophages augments bacterial killing by promoting phagocytosis. Am J Pathol. 2011 Jun;178(6):2752-9. PMID: 21641397
- Ramsgaard L, Englert JM, Manni ML, Milutinovic PS, Gefter J, Tobolewski J, Crum L, Coudriet GM, Piganelli JD, Zamora R, Vodovotz Y, Enghild JJ, Oury TD. Lack of the Receptor for Advanced Glycation End-Products Attenuates E. coli Pneumonia in Mice. PLoS One. 2011;6(5):e20132. Epub 2011 May 23. PMID: 21629785
- Hager EJ, Piganelli JD, Tse HM, Gibson KM. Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). J Inherit Metab Dis. 2012 Volume 35, Number 1, 159-168. PMID: 21607759
- Coudriet GM, He J, Trucco M, Mars WM, Piganelli JD. Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS One. 2010 Nov 2;5(11):e15384. PMID: 21072211
- Chen J, Gusdon AM, Piganelli JD, Leiter EH, Mathews CE. mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic β-cell. Diabetes. 2011 Jan;60(1):355-9. Epub 2010 Oct 27. PMID: 20980458
- Tse HM, Thayer TC, Steele C, Cuda CM, Morel L, Piganelli JD, Mathews CE. NADPH oxidase deficiency regulates Th lineage commitment and modulates autoimmunity. J Immunol. 2010 Nov 1;185(9):5247-58. Epub 2010 Sep 29. PMID: 20881184
- Batinic-Haberle I, Spasojevic I, Tse HM, Tovmasyan A, Rajic Z, St Clair DK, Vujaskovic Z, Dewhirst MW, Piganelli JD. Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities. Amino Acids. 2010 May 16. Amino Acids. 2012 Jan;42(1):115-6 . [Epub ahead of print] PMID: 20473774
- Sklavos MM, Bertera S, Tse HM, Bottino R, He J, Beilke JN, Coulombe MG, Gill RG, Crapo JD, Trucco M, Piganelli JD. Redox modulation protects islets from transplant-related injury. Diabetes. 2010 Jul;59(7):1731-8. Epub 2010 Apr 22. PMID 20413509
- Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradley B, Crawford F, Marrack P, Mahata SK, Kappler JW, Haskins K. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010 Mar;11(3):225-31. Epub 2010 Feb 7. PMID: 20139986
- Schulte BM, Kramer M, Ansems M, Lanke KH, van Doremalen N, Piganelli JD, Bottino R, Trucco M, Galama JM, Adema GJ, van Kuppeveld FJ. Phagocytosis of enterovirus-infected pancreatic beta-cells triggers innate immune responses in human dendritic cells. Diabetes. 2010 May;59(5):1182-91. Epub 2010 Jan 13.PMID: 20071599
- Su D, Coudriet GM, Hyun Kim D, Lu Y, Perdomo G, Qu S, Slusher S, Tse HM, Piganelli JD, Giannoukakis N, Zhang J, Henry Dong H. FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages. Diabetes. 2009 Nov;58(11):2624-33. Epub 2009 Aug 3. PMID: 19651810
- Sheng H, Yang W, Fukuda S, Tse HM, Paschen W, Johnson K, Batinic-Haberle I, Crapo JD, Pearlstein RD, Piganelli JD, Warner DS. Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat. Free Radic Biol Med. 2009 Oct 1;47(7):917-23. Epub 2009 Jul 22. PMID:19631268
- Urish KL, Vella JB, Okada M, Deasy BM, Tobita K, Keller BB, Cao B, Piganelli JD, Huard J. Antioxidant levels represent a major determinant in the regenerative capacity of muscle stem cells. Mol Biol Cell. 2009 Jan;20(1):509-20. Epub 2008 Nov 12. PMID: 19005220
- Sklavos MM, Tse HM, Piganelli JD. Redox modulation inhibits CD8 T cell effector function. Free Radic Biol Med. 2008 Nov 15;45(10):1477-86. Epub 2008 Sep 9. PMID: 18805480
- Small Group Facilitator Foundations
- Methods and Logic in Medicine, Facilitator
- Molecular Pathobiology. Diabetes Section Director on Clinical Research in the Management and Treatment of Diabetes Mellitus
- Autoimmunity, Inflammatory Mediated Diseases, reactive oxygen species (ROS) signlaing