Human cord blood stem cell-modulated regulatory T lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (NOD) mice
Yong Zhao, Brian Lin, Robert Darflinger, Yongkang Zhang, Mark J Holterman, Randal A Skidgel, Yong Zhao, Brian Lin, Robert Darflinger, Yongkang Zhang, Mark J Holterman, Randal A Skidgel
Abstract
Background: The deficit of pancreatic islet beta cells caused by autoimmune destruction is a crucial issue in type 1 diabetes (T1D). It is essential to fundamentally control the autoimmunity for treatment of T1D. Regulatory T cells (Tregs) play a pivotal role in maintaining self-tolerance through their inhibitory impact on autoreactive effector T cells. An abnormality of Tregs is associated with initiation of progression of T1D.
Methodology/principal findings: Here, we report that treatment of established autoimmune-caused diabetes in NOD mice with purified autologous CD4(+)CD62L(+) Tregs co-cultured with human cord blood stem cells (CB-SC) can eliminate hyperglycemia, promote islet beta-cell regeneration to increase beta-cell mass and insulin production, and reconstitute islet architecture. Correspondingly, treatment with CB-SC-modulated CD4(+)CD62L(+) Tregs (mCD4CD62L Tregs) resulted in a marked reduction of insulitis, restored Th1/Th2 cytokine balance in blood, and induced apoptosis of infiltrated leukocytes in pancreatic islets.
Conclusions/significance: These data demonstrate that treatment with mCD4CD62L Tregs can reverse overt diabetes, providing a novel strategy for the treatment of type 1 diabetes as well as other autoimmune diseases.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Trucco M. Regeneration of the pancreatic beta cell. J Clin Invest. 2005;115:5–12.
- Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A. 2003;100:2426–2431.
- Zhao Y, Wang H, Mazzone T. Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics. Exp Cell Res. 2006;312:2454–2464.
- Ricordi C, Hering BJ, Shapiro AM. Beta-cell transplantation for diabetes therapy. Lancet. 2008;372:27–28.
- Ablamunits V, Sherry NA, Kushner JA, Herold KC. Autoimmunity and beta cell regeneration in mouse and human type 1 diabetes: the peace is not enough. Ann N Y Acad Sci. 2007;1103:19–32.
- Bonner-Weir S, Weir GC. New sources of pancreatic beta-cells. Nat Biotechnol. 2005;23:857–861.
- Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008
- Bluestone JA, Tang Q, Sedwick CE. T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects. J Clin Immunol 2008
- Bresson D, Togher L, Rodrigo E, Chen Y, Bluestone JA, et al. Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs. J Clin Invest. 2006;116:1371–1381.
- Chatenoud L, Bach JF. Resetting the functional capacity of regulatory T cells: a novel immunotherapeutic strategy to promote immune tolerance. Expert Opin Biol Ther. 2005;5(Suppl 1):S73–S81.
- Chatenoud L, Bach JF. Regulatory T cells in the control of autoimmune diabetes: the case of the NOD mouse. Int Rev Immunol. 2005;24:247–267.
- Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7:585–598.
- Tarbell KV, Petit L, Zuo X, Toy P, Luo X, et al. Dendritic cell-expanded, islet-specific CD4+CD25+CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204:191–201.
- You S, Slehoffer G, Barriot S, Bach JF, Chatenoud L. Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14580–14585.
- Li Q, Xu B, Michie SA, Rubins KH, Schreriber RD, et al. Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008;105:12439–12444.
- Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+FOXP3+ regulatory T cells. J Immunol. 2008;181:7350–7355.
- Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28:687–697.
- Zehn D, Bevan MJ. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity. 2006;25:261–270.
- Allen JS, Pang K, Skowera A, Ellis R, Rackham C, et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of Type 1 diabetes and enhance islet autoantigen presentation to T cells through immune complex capture. Diabetes 2008
- Huang Y, Fugier-Vivier IJ, Miller T, Elliott MJ, Xu H, et al. Plasmacytoid precursor dendritic cells from NOD mice exhibit impaired function: are they a component of diabetes pathogenesis? Diabetes. 2008;57:2360–2370.
- Jin Y, Chen X, Podolsky R, Hopkins D, Makala LH, et al. APC dysfunction is correlated with defective suppression of T cell proliferation in human type 1 diabetes. Clin Immunol 2008
- Marleau AM, Summers KL, Singh B. Differential contributions of APC subsets to T cell activation in nonobese diabetic mice. J Immunol. 2008;180:5235–5249.
- Summers KL, Marleau AM, Mahon JL, McManus R, Hramiak I, et al. Reduced IFN-alpha secretion by blood dendritic cells in human diabetes. Clin Immunol. 2006;121:81–89.
- Kukreja A, Cost G, Marker J, Zhang C, Sun Z, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002;109:131–140.
- Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R. Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J Exp Med. 2005;201:1333–1346.
- You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, et al. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes. 2005;54:1415–1422.
- Bayry J, Lacroix-Desmazes S, Dasgupta S, Kazatchkine MD, Kaveri SV. Efficacy of regulatory T-cell immunotherapy: are inflammatory cytokines key determinants? Nat Rev Immunol. 2008;8:1p.
- Brusko T, Wasserfall C, McGrail K, Schatz R, Viener HL, et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes. 2007;56:604–612.
- Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+CD25+ T-cells in type 1 diabetes. Diabetes. 2005;54:1407–1414.
- Gombert JM, Herbelin A, Tancrede-Bohin E, Dy M, Chatenoud L, et al. Early defect of immunoregulatory T cells in autoimmune diabetes. C R Acad Sci III. 1996;319:125–129.
- Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, et al. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–99.
- Tritt M, Sgouroudis E, d'Hennezel E, Albanese A, Piccirillo CA. Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes. 2008;57:113–123.
- Zhao Y, Huang Z, Qi M, Lazzarini P, Mazzone T. Immune regulation of T lymphocyte by a newly characterized human umbilical cord blood stem cell. Immunol Lett. 2007;108:78–87.
- Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57:1759–1767.
- Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, et al. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia. 2006;49:1838–1844.
- Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134:392–404.
- Roncarolo MG, Battaglia M, Gregori S. The role of interleukin 10 in the control of autoimmunity. J Autoimmun. 2003;20:269–272.
- Wan YY, Flavell RA. The roles for cytokines in the generation and maintenance of regulatory T cells. Immunol Rev. 2006;212:114–130.
- Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med. 2008;14:528–535.
- Staeva-Vieira T, Peakman M, von HM. Translational mini-review series on type 1 diabetes: Immune-based therapeutic approaches for type 1 diabetes. Clin Exp Immunol. 2007;148:17–31.
- Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–3506.
- Bour-Jordan H, Salomon BL, Thompson HL, Santos R, Abbas AK, et al. Constitutive expression of B7-1 on B cells uncovers autoimmunity toward the B cell compartment in the nonobese diabetic mouse. J Immunol. 2007;179:1004–1012.
- Goudy KS, Burkhardt BR, Wasserfall C, Song S, Campbell-Thompson ML, et al. Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J Immunol. 2003;171:2270–2278.
Source: PubMed