Research Article

Preliminary Report on the Effect of Mesenchymal Stem Cell Therapy in Patients with Chronic Lung Allograft Dysfunction

Cesar A Keller*, Thomas A Gonwa, Athena L Russell, David O Hodge, David B Erasmus and Abba C Zubair

Published: 28 August, 2018 | Volume 2 - Issue 1 | Pages: 035-047

Background: Mesenchymal stem cell (MSC) effects can shift immune responses toward anti-inflammatory and tolerogenic phenotypes, potentially helping patients with bronchiolitis obliterans syndrome (BOS).

Methods: We evaluated the effect of infusing allogeneic MSC intravenously in 9 patients with moderate BOS refractory to standard therapy who were not candidates for retransplant, dividing them into 3 dosing groups: Group 1, 1×106 MSC/kg (n=3); Group 2, 2×106 MSC/kg (n=3); and Group 3, 4×106 MSC/kg (n=3). We recorded pulmonary function tests, laboratory variables, and serum biomarkers pre- and post-MSC infusion.

Results: These patients had significant decline in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) over 1 year pre-MSC infusion (mean ± SD) FVC, 3.11±0.98 L, and FEV1 1.99+0.64 L versus FVC 2.58±1.03 and FEV1 1.61±0.52 just before infusion (P<0.05); representing a mean loss of 530 mL in FVC and 374 mL in FEV1 over 12 months. One year post-MSC infusion, mean FVC and FEV1 increased to 2.66±1.01 L and 1.63±0.55 L, respectively (changes no longer significant compared to before MSC infusion). Patients in Group 1 showed elevation of tolerance-inducing T regulatory cells and increased levels of epidermal growth factor. Tolerance-inducing Th-2 cytokines increased in Groups 1 and 2. These changes were not significantly different in these small sub-groups.

Conclusion: MSC infusion appears to slow down or reverse the progressive decline in lung function in some patients with moderate BOS, possibly by inducing anti-inflammatory effects and promoting cell proliferation and angiogenesis.

Read Full Article HTML DOI: 10.29328/journal.jsctt.1001012 Cite this Article Read Full Article PDF


Bronchiolitis obliterans syndrome; Lung transplantation; Mesenchymal stem cells; Obstructive CLAD


  1. Weill D, Benden C, Corris PA, Dark JH, Davis RD, et al. A consensus document for the selection of lung transplant candidates. 2014-An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015; 34: 1-15. Ref.: https://tinyurl.com/yb6tufvh
  2. Christie JD, Sager JS, Kimmel SE, Ahya VN, Gaughan C, et al. Impact of primary graft failure on outcomes following lung transplantation. Chest. 2005; 127: 161-165. Ref.: https://tinyurl.com/y9fras99
  3. Burguete SR, Maselli DJ, Fernandez JF, Levine SM. Lung transplant infection. Respirology. 2013; 18: 22-38. Ref.: https://tinyurl.com/y9wj5gqw
  4. Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc. 2009; 6: 54-65. Ref.: https://tinyurl.com/yawkc6gb
  5. Witt CA, Gaut JP, Yusen RD, Byers DE, Iuppa JA, et al. Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant. 2013; 32: 1034-1040. Ref.: https://tinyurl.com/y9gczlm9
  6. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014; 33: 127-133. Ref.: https://tinyurl.com/ydgul2j6
  7. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002; 21: 297-310. Ref.: https://tinyurl.com/y84ovdha 
  8. Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011; 30: 735-742. Ref.: https://tinyurl.com/yaau27zu
  9. Lin CM, Zamora MR. Update on Bronchiolitis Obliterans Syndrome in Lung Transplantation. Curr Transplant Rep. 2014; 1: 282-289. Ref.: https://tinyurl.com/ybx4294d
  10. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014; 44: 1479-1503. Ref.: https://tinyurl.com/ybk8acgu
  11. Belperio JA, Weigt SS, Fishbein MC, Lynch JP. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc. 2009; 6: 108-121. Ref.: https://tinyurl.com/yc954hm6
  12. Corris PA, Ryan VA, Small T, Lordan J, Fisher AJ, et al. A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. Thorax. 2015; 70: 442-450. Ref.: https://tinyurl.com/yc82wn6o
  13. Davis RD Jr, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003; 125: 533-542. Ref.: https://tinyurl.com/yc4kcfue
  14. Novick RJ, Stitt LW, Al-Kattan K, Benden C, Dipchand AI, et al. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Pulmonary Retransplant Registry. Ann Thorac Surg. 1998; 65: 227-234. Ref.: https://tinyurl.com/y88mcnao
  15. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant. 2014; 33: 1009-1024. Ref.: https://tinyurl.com/ydg67cab
  16. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2: 141-150. Ref.: https://tinyurl.com/y8pbzr7b
  17. Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy. 2009; 11: 377-391. Ref.: https://tinyurl.com/y7a3jha9
  18. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008; 111: 1327-1333. Ref.: https://tinyurl.com/y735osx8
  19. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009; 18: 683-692. Ref.: https://tinyurl.com/ycsx76nv
  20. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 2003; 100: 8407-8411. Ref.: https://tinyurl.com/ycnna3hj
  21. Weng JY, Du X, Geng SX, Peng YW, Wang Z, et al. Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant. 2010; 45: 1732-1740. Ref.: https://tinyurl.com/ycwo94wq
  22. Chambers DC, Enever D, Lawrence S, Sturm MJ, Herrmann R, et al. Mesenchymal Stromal Cell Therapy for Chronic Lung Allograft Dysfunction: Results of a First-in-Man Study. Stem Cells Transl Med. 2017; 6: 1152-1157. Ref.: https://tinyurl.com/yaq4q64v 
  23. Keller CA, Erasmus DB, Alvarez FG, Mallea JM, Hurst KE, et al. Preliminary Report on the Effect of Mesenchymal Stem Cell (MSC) Infusion in Lung Function on Patients with Chronic Allograft Dysfunction (CLAD). J Heart Lung Transplant. 2016; 35: S43. Ref.: https://tinyurl.com/ybg72jjy
  24. Keller CA, Gonwa TA, Hodge DO, Hei DJ, Centanni JM, et al. Feasibility, Safety, and Tolerance of Mesenchymal Stem Cell Therapy for Obstructive Chronic Lung Allograft Dysfunction. Stem Cells Transl Med. 2018; 7: 161-167. Ref.: https://tinyurl.com/ybwn9py6
  25. Mesenchymal Stem Cell Therapy for Lung Rejection. 2014.
  26. Rojas M, Xu J, Woods CR, Mora AL, Spears W, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005; 33: 145-152. Ref.: https://tinyurl.com/y7559mfc
  27. Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012; 3: 359. Ref.: https://tinyurl.com/y7utwtsg
  28. Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009; 60: 813-823. Ref.: https://tinyurl.com/y84qm9cq
  29. Schenk S, Mal N, Finan A, Zhang M, Kiedrowski M, et al. Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells. 2007; 25: 245-251. Ref.: https://tinyurl.com/ycl3lfzh
  30. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002; 30: 42-48. Ref.: https://tinyurl.com/y78huexv
  31. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood. 2005; 106: 1755-1761. Ref.: https://tinyurl.com/yb7fyw9x
  32. Kim SW, Zhang HZ, Guo L, Kim JM, Kim MH. Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities. PLoS One. 2012; 7: e41105. Ref.: https://tinyurl.com/jpdqco6
  33. Khalili S, Liu Y, Kornete M, Nienke R, Shohta K, et al. Mesenchymal stromal cells improve salivary function and reduce lymphocytic infiltrates in mice with Sjogren's-like disease. PLoS One. 2012; 7: e38615. Ref.: https://tinyurl.com/y72dvv9e
  34. Perin EC, Borow KM, Silva GV, DeMaria AN, Marroquin OC, et al. A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure. Circ Res. 2015; 117: 576-584. Ref.: https://tinyurl.com/yambss9v
  35. Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009; 15: 804-811. Ref.: https://tinyurl.com/yao3qxue
  36. Reichenspurner H, Girgis RE, Robbins RC, Conte JV, Nair RV, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1995; 60: 1845-1853. Ref.: https://tinyurl.com/yab268gm
  37. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006; 81: 1390-1397. Ref.: https://tinyurl.com/y8l2tp2k
  38. Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013; 143: 1590-1598. Ref.: https://tinyurl.com/y89bknpb
  39. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015; 3: 24-32. Ref.: https://tinyurl.com/y76yz9p9


Figure 1

Figure 1

Figure 1

Figure 2

Figure 1

Figure 3

Figure 1

Figure 4

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More