Allogenic Adipose Tissue-Derived Stromal/Stem Cells and Vitamin D Supplementation in Patients With Recent-Onset Type 1 Diabetes Mellitus: A 3-Month Follow-Up Pilot Study

Debora B Araujo, Joana R Dantas, Karina R Silva, Débora L Souto, Maria de Fátima C Pereira, Jessica P Moreira, Ronir R Luiz, Cesar S Claudio-Da-Silva, Monica A L Gabbay, Sergio A Dib, Carlos E B Couri, Angelo Maiolino, Carmen L K Rebelatto, Debora R Daga, Alexandra C Senegaglia, Paulo R S Brofman, Leandra Santos Baptista, José E P Oliveira, Lenita Zajdenverg, Melanie Rodacki, Debora B Araujo, Joana R Dantas, Karina R Silva, Débora L Souto, Maria de Fátima C Pereira, Jessica P Moreira, Ronir R Luiz, Cesar S Claudio-Da-Silva, Monica A L Gabbay, Sergio A Dib, Carlos E B Couri, Angelo Maiolino, Carmen L K Rebelatto, Debora R Daga, Alexandra C Senegaglia, Paulo R S Brofman, Leandra Santos Baptista, José E P Oliveira, Lenita Zajdenverg, Melanie Rodacki

Abstract

Objective: To evaluate the short term safety and potential therapeutic effect of allogenic adipose tissue-derived stromal/stem cells (ASCs) + cholecalciferol in patients with recent-onset T1D. Methods: Prospective, phase II, open trial, pilot study in which patients with recent onset T1D received ASCs (1 × 106 cells/kg) and cholecalciferol 2000 UI/day for 3 months (group 1) and were compared to controls with standard insulin therapy (group 2). Adverse events, C-peptide (CP), insulin dose, HbA1c, time in range (TIR), glucose variability (continuous glucose monitoring) and frequency of CD4+FoxP3+ T-cells (flow cytometry) were evaluated at baseline (T0) and after 3 months (T3). Results: 13 patients were included (8: group 1; 5: group 2). Their mean age and disease duration were 26.7 ± 6.1 years and 2.9 ± 1.05 months. Adverse events were transient headache (n = 8), mild local reactions (n = 7), tachycardia (n = 4), abdominal cramps (n = 1), thrombophlebitis (n = 4), mild floaters (n = 2), central retinal vein occlusion (n = 1, complete resolution). At T3, group 1 had lower insulin requirement (0.22 ± 0.17 vs. 0.61±0.26IU/Kg; p = 0.01) and HbA1c (6.47 ± 0.86 vs. 7.48 ± 0.52%; p = 0.03) than group 2. In group 1, 2 patients became insulin free (for 4 and 8 weeks) and all were in honeymoon at T3 (vs. none in group 2; p = 0.01). CP variations did not differ between groups (-4.6 ± 29.1% vs. +2.3 ± 59.65%; p = 0.83). Conclusions: Allogenic ASCs + cholecalciferol without immunosuppression was associated with stability of CP and unanticipated mild transient adverse events in patients with recent onset T1D. ClinicalTrials.gov registration: NCT03920397.

Keywords: adipose tissue-derived stromal/stem cells; pancreatic function; transplant; type 1 diabetes; vitamin D.

Copyright © 2020 Araujo, Dantas, Silva, Souto, Pereira, Moreira, Luiz, Claudio-Da-Silva, Gabbay, Dib, Couri, Maiolino, Rebelatto, Daga, Senegaglia, Brofman, Baptista, Oliveira, Zajdenverg and Rodacki.

Figures

Figure 1
Figure 1
Flow Diagram of the clinical trial.
Figure 2
Figure 2
Characterization of adipose tissue-derived stromal/stem cells. (A) Adipose tissue-derived stromal/stem cells morphology. (B) BM-MSC differentiation. Cells were incubated for 21 days in the presence of specific differentiation agents for adipocytes, osteoblasts and chondrocytes. Differentiation into adipocyte lineage was demonstrated by staining with Oil Red O (B4), Alizarin Red S staining shows mineralization of the extracellular matrix in osteogenic differentiation (B5) and toluidine blue shows the deposition of proteoglycans and lacunaes in chondrogenic differentiation (B6). Untreated control cultures without adipogenic, osteogenic or chondrogenic differentiation stimuli are shown (B1–B3). (C) Representative figure of the flow cytometric analysis. The red line indicates isotype control and the blue line represent.
Figure 3
Figure 3
Levels of HbA1C, insulin dose and C-Peptide during follow-up. The levels were evaluated on blood samples before (T0) and three (T3) months after ASCs infusion. Group 1 presented lower HbA1C (p = 0.03) and insulin dose (p = 0.01) in comparison to group 2. Group 1 presented similar CP AUC (p = 0.06) in comparison to group 2.
Figure 4
Figure 4
Variation of FoxP3+ cells among CD45+CD3+CD8+ cells. The levels of T-cells were evaluated on blood samples before (T0), one (T1) and three (T3) months after ASCs infusion. (A) Individual variation of FoxP3+ cells among CD45+CD3+CD8+ cells of group 1. (B) Individual variation of FoxP3+ cells among CD45+CD3+CD8+ cells of group 2. At T1, group 1 presented a higher frequency of CD45+CD3+CD8+FoxP3+ cells in comparison to group 2 (p = 0.03). At T0 and T3 no significant difference was found (p = 0.17 and p = 1.00, respectively).

References

    1. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. (2001) 358:221–9. 10.1016/S0140-6736(01)05415-0
    1. Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes. (2005) 54(Suppl. 2):S25–31. 10.2337/diabetes.54.suppl_2.S25
    1. Couri CEB, de Oliveira MC, Simões BP. Risks, benefits, and therapeutic potential of hematopoietic stem cell transplantation for autoimmune diabetes. Curr Diabetes Rep. (2012) 12:604–11. 10.1007/s11892-012-0309-0
    1. Dantas JR, Almeida MH, Barone B, Serfaty F, Raggio LR, Kupfer R, et al. . Continuous C-peptide loss in patients with type 1 diabetes and multiethnic background. Diabetes Res Clin Pract. (2013) 99:e33–6. 10.1016/j.diabres.2012.12.019
    1. Rodacki M, Milech A, de Oliveira JEP. A secreção residual do peptídeo C faz diferença no tratamento do diabetes melito tipo 1? Arq Bras Endocrinol Metab. (2008) 52:322–33. 10.1590/S0004-27302008000200020
    1. Fiorina P, Voltarelli J, Zavazava N. Immunological applications of stem cells in type 1 diabetes. Endocr Rev. (2011) 32:725–54. 10.1210/er.2011-0008
    1. Lernmark Å, Larsson HE. Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol. (2013) 9:92–103. 10.1038/nrendo.2012.237
    1. Rydén AK, Wesley JD, Coppieters KT, Von Herrath MG. Non-antigenic and antigenic interventions in type 1 diabetes. Hum Vaccines Immunother. (2014) 10:838–46. 10.4161/hv.26890
    1. Davis IC, Randell J, Davis SN. Immunotherapies currently in development for the treatment of type 1 diabetes. Expert Opin Invest Drugs. (2015) 24:1331–41. 10.1517/13543784.2015.1075973
    1. Vudattu NK, Herold KC. Treatment of new onset type 1 diabetes with teplizumab: successes and pitfalls in development. Expert Opin Biol Ther. (2014) 14:377–85. 10.1517/14712598.2014.881797
    1. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. . Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. (2009) 361:2143–52. 10.1056/NEJMoa0904452
    1. Marmont AM. Coincidental autoimmune disease in patients transplanted for conventional indications. Best Pract Res Clin Haematol. (2004) 17:223–32. 10.1016/j.beha.2004.04.004
    1. Kuhn C, Besançon A, Lemoine S, You S, Marquet C, Candon S, et al. . Regulatory mechanisms of immune tolerance in type 1 diabetes and their failures. J Autoimmun. (2016) 71:69–77. 10.1016/j.jaut.2016.05.002
    1. Okubo Y, Torrey H, Butterworth J, Zheng H, Faustman DL. Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Clin Trans Immunol. (2016) 5:e56. 10.1038/cti.2015.43
    1. Hamari S, Kirveskoski T, Glumoff V, Kulmala P, Simell O, Knip M, et al. . Analyses of regulatory CD4 + CD25 + FOXP3 + T cells and observations from peripheral T cell subpopulation markers during the development of type 1 diabetes in children. Scand J Immunol. (2016) 83:279–87. 10.1111/sji.12418
    1. 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) 57:1759–67. 10.2337/db08-0180
    1. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, et al. . Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA. (2006) 103:17438–43. 10.1073/pnas.0608249103
    1. Baptista LS, do Amaral RJFC, Carias RBV, Aniceto M, Claudio-da-Silva C, Borojevic R. An alternative method for the isolation of mesenchymal stromal cells derived from lipoaspirate samples. Cytotherapy. (2009) 11:706–15. 10.3109/14653240902981144
    1. García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of crohn's fistula by adipose mesenchymal stem cell transplantation: diseases of the colon & rectum. Dis Colon Rectum. (2005). 48:1416–23. 10.1007/s10350-005-0052-6
    1. Gan J, Wang Y, Zhou X. Stem cell transplantation for the treatment of patients with type1 diabetes mellitus: a meta-analysis. Exp Ther Med. (2018) 16:4479–92. 10.3892/etm.2018.6769
    1. Rivera-Izquierdo M, Cabeza L, Láinez-Ramos-Bossini A, Quesada R, Perazzoli G, Alvarez P, et al. . An updated review of adipose derived-mesenchymal stem cells and their applications in musculoskeletal disorders. Expert Opin Biol Ther. (2019) 19:233–48. 10.1080/14712598.2019.1563069
    1. Georgiev-Hristov T, Guadalajara H, Herreros MD, Lightner AL, Dozois EJ, García-Arranz M, et al. . A step-by-step surgical protocol for the treatment of perianal fistula with adipose-derived mesenchymal stem cells. J Gastrointest Surg. (2018) 22:2003–12. 10.1007/s11605-018-3895-6
    1. De Jesus MM, Santiago JS, Trinidad CV, See ME, Semon KR, Fernandez MO, Jr., et al. . Autologous adipose-derived mesenchymal stromal cells for the treatment of psoriasis vulgaris and psoriatic arthritis: a case report. Cell Transplant. (2016) 25:2063–9. 10.3727/096368916X691998
    1. Maria AT, Maumus M, Le Quellec A, Jorgensen C, Noël D, Guilpain P. Adipose-derived mesenchymal stem cells in autoimmune disorders: state of the art and perspectives for systemic sclerosis. Clin Rev Allergy Immunol. (2017) 52:234–59. 10.1007/s12016-016-8552-9
    1. Daumas A, Magalon J, Jouve E, Truillet R, Casanova D, Giraudo L, et al. . Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients. Curr Res Transl Med. (2017). 65:40–3. 10.1016/j.retram.2016.10.006
    1. Riachy R, Vandewalle B, Kerr Conte J, Moerman E, Sacchetti P, Lukowiak B, et al. . 1,25-dihydroxy vitamin D 3 protects RINm5F and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein a20. Endocrinology. (2002) 143:4809–19. 10.1210/en.2002-220449
    1. Al-Zubeidi H, Leon-Chi L, Newfield RS. Low vitamin D level in pediatric patients with new onset type 1 diabetes is common, especially if in ketoacidosis: Vitamin D in new onset Type 1 Diabetes. Pediatr Diabetes. (2016) 17:592–8. 10.1111/pedi.12342
    1. Treiber G, Prietl B, Fröhlich-Reiterer E, Lechner E, Ribitsch A, Fritsch M, et al. . Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - a randomized clinical trial. Clin Immunol. (2015) 161:217–24. 10.1016/j.clim.2015.08.002
    1. Gregoriou E, Mamais I, Tzanetakou I, Lavranos G, Chrysostomou S. The effects of vitamin D supplementation in newly diagnosed type 1 diabetes patients: systematic review of randomized controlled trials. Rev Diabet Stud. (2017) 14:260–8. 10.1900/RDS.2017.14.260
    1. Gabbay MAL, Sato MN, Finazzo C, Duarte AJ, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adol Med. (2012) 166:601–7. 10.1001/archpediatrics.2012.164
    1. Thorsen SU, Mortensen HB, Carstensen B, Fenger M, Thuesen BH, Husemoen L, et al. . No association between type 1 diabetes and genetic variation in vitamin D metabolism genes: a Danish study: T1D and SNPs in vitamin D metabolism genes. Pediatr Diabetes. (2014) 15:416–21. 10.1111/pedi.12105
    1. Vija L, Farge D, Gautier J-F, Vexiau P, Dumitrache C, Bourgarit A, et al. . Mesenchymal stem cells: stem cell therapy perspectives for type 1 diabetes. Diabetes Metab. (2009) 35:85–93. 10.1016/j.diabet.2008.10.003
    1. Cai J, Wu Z, Xu X, Liao L, Chen J, Huang L, et al. . Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care. (2016) 39:149–57. 10.2337/dc15-0171
    1. Trivedi HL, Vanikar AV, Thakker U, Firoze A, Dave SD, Patel CN, et al. . Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Transpl Proc. (2008) 40:1135–9. 10.1016/j.transproceed.2008.03.113
    1. Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, et al. . Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. (2007) 297:1568–76. 10.1001/jama.297.14.1568
    1. Sokołowska M, Chobot A, Jarosz-Chobot P. Department of pediatrics, the upper silesian child health center, the honeymoon phase - what we know today about the factors that can modulate the remission period in type 1 diabetes. Pediatr Endocr Diabetes Metab. (2016) 22:66–70. 10.18544/PEDM-22.02.0053
    1. Langendam M, Luijf YM, Hooft L, DeVries JH, Mudde AH, Scholten RJ. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Datab Syst Rev. (2012) 1:CD008101. 10.1002/14651858.CD008101.pub2
    1. Kohnert K-D, Heinke P, Fritzsche G, Vogt L, Augstein P, Salzsieder E. Evaluation of the mean absolute glucose change as a measure of glycemic variability using continuous glucose monitoring data. Diabetes Technol Ther. (2013) 15:448–54. 10.1089/dia.2012.0303
    1. Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther. (2011) 13:921–8. 10.1089/dia.2010.0247
    1. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. . Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. (2019) 42:1593–603. 10.2337/dci19-0028
    1. Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, et al. . Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. (2013) 36:3821–42. 10.2337/dc13-2042
    1. Wang Y, Wu S, Wen F, Cao Q. Diabetes mellitus as a risk factor for retinal vein occlusion: a meta-analysis. Medicine. (2020) 99:e19319. 10.1097/MD.0000000000019319
    1. Yoo YS, Na KS, Shin JA, Park YH, Lee JW. Posterior eye segment complications related to allogeneic hematopoietic stem cell transplantation. Retina. (2017) 37:135–43. 10.1097/IAE.0000000000001122
    1. Zhang Y, Chen W, Feng B, Cao H. The clinical efficacy and safety of stem cell therapy for diabetes mellitus: a systematic review and meta-analysis. Aging Dis. (2020) 11:141–53. 10.14336/AD.2019.0421
    1. Bertuzzi F, De Carlis L, Marazzi M, Rampoldi AG, Bonomo M, Antonioli B, et al. . Long-term effect of islet transplantation on glycemic variability. Cell Transplant. (2018) 27:840–6. 10.1177/0963689718763751
    1. Hugle T, Daikeler T. Stem cell transplantation for autoimmune diseases. Haematologica. (2010) 95:185–8. 10.3324/haematol.2009.017038
    1. Rickels MR, Evans-Molina C, Bahnson HT, Ylescupidez A, Nadeau KJ, Hao W, et al. . High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J Clin Invest. (2020) 130:1850–62. 10.1172/JCI134057
    1. Redondo MJ, Connor CG, Ruedy KJ, Beck RW, Kollman C, Wood JR, et al. . Pediatric diabetes consortium type 1 diabetes new onset (NeOn) study: factors associated with HbA1c levels one year after diagnosis: characteristics associated with HbA1c. Pediatr Diabetes. (2014) 15:294–302. 10.1111/pedi.12061
    1. Christoffersson G, von Herrath M. Regulatory immune mechanisms beyond regulatory T cells. Trends Immunol. (2019) 40:482–91. 10.1016/j.it.2019.04.005
    1. Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC. TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest. (2005) 115:2904–13. 10.1172/JCI23961
    1. Hagopian W, Ferry RJ, Jr., Sherry N, Carlin D, Bonvini E, Johnson S, et al. . Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. (2013) 62:3901–8. 10.2337/db13-0236
    1. Aronson R, Gottlieb PA, Christiansen JS, Donner TW, Bosi E, Bode BW, et al. . Low-dose otelixizumab anti-CD3 monoclonal antibody DEFEND-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. Diabetes Care. (2014) 37:2746–54. 10.2337/dc13-0327

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