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Editorial |

Alveolar Type 2 Cell Transplantation in IPF: Recreating the Silver Lining FREE TO VIEW

Namrata B. Patel, MD; Jason D. Christie, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: N. B. T. has served as a consultant for InterMune. J. D. C. has received institutional funding from BristolMyersSquibb for an epidemiological study of pulmonary fibrosis.

Pulmonary, Critical Care, and Allergy Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

CORRESPONDENCE TO: Namrata Patel, MD, Pulmonary, Critical Care, and Allergy Division, Perelman School of Medicine at the University of Pennsylvania, 831 Gates Bldg, 3400 Spruce St, Philadelphia PA, 19104


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(3):481-482. doi:10.1016/j.chest.2016.05.036
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Published online

After decades of failed therapies, mechanistic insights have led to the development of therapies successful in curtailing, but not abrogating, the fibrosis that results in the devastating clinical course of patients with idiopathic pulmonary fibrosis (IPF). Alveolar epithelium undergoing injury from various agents such as inhalation exposures, gastroesophageal reflux, DNA viruses, and mechanisms of oxidative stress can stimulate stress response pathways, mediator release, and apoptosis. This abnormally activated epithelium is thought to promote fibroblast recruitment and activation, which leads to matrix deposition and fibroblast persistence. It follows that there is a growing interest in creating cell-based therapies to help restore a normal wound-healing response.

FOR RELATED ARTICLE SEE PAGE 533

Mesenchymal stromal cells (MSCs) are attractive candidates for such study, given their multipotency and relative immune privilege, permitting allotransplantation without immunomodulation. Preclinical animal model studies have been generally favorable, and the limited experience in subjects with IPF suggests a reasonable tolerability.,, The therapeutic effectiveness of MSC transplantation remains to be established; there is skepticism based on both their transient retention in the pulmonary vascular bed, calling into question the longevity of any salutatory effects, and the possibility that MSCs can stimulate fibroblasts to proliferate and deposit extracellular matrix through the Wnt protein and transforming growth factor β1 pathways., A randomized blinded placebo controlled study of MSC transplantation aiming to examine the safety as well as the impact on lung function and quality of life is under way.

The study by Serrano-Mollar and colleagues in this issue of CHEST is a welcome example of novel cell-based therapy using alveolar type II (ATII) cells. In the study, the authors examined the safety and tolerability of transplanting ATII cells in an effort to replenish the alveolar epithelium with the hopes of curtailing and perhaps reversing the fibrotic process. The rationale for this approach was presented in their prior work demonstrating the feasibility of purification and delivery of ATII cells through intratracheal instillation in a Lewis rat model of bleomycin–induced lung fibrosis. The presence of donor-derived ATII cells in the alveoli of female recipients was confirmed by detection of the Y chromosome in the male donor cell population. Injured lungs evaluated 15 days after transplantation with ATII cells demonstrated reductions in the severity of histologic scarring and collagen deposition.

In the current study, the investigators selected patients with IPF, 75 years of age or younger with a FVC ≥ 50% predicted and diffusing capacity of lung for carbon monoxide ≥ 35% predicted who were in a “progressive phase” of their disease, as evidenced by increased dyspnea, an increase in the extent of disease by high-resolution CT, a FVC decline of ≥ 10% or a decline in diffusing capacity of lung for carbon monoxide ≥ 15% in the previous year. The patients underwent instillation of ATII cells, procured from ABO-compatible organ donors, through four sequential bronchoscopies 15 days apart. Given the potential for immune recognition and rejection of these cells, unlike with MSC transplantation, the patients underwent immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone, as well as antimicrobial prophylaxis with trimethoprim-sulfamethoxazole and valganciclovir. The procedure was well tolerated, with the exception of one patient who experienced an infiltrate and hypoxemia that was treated effectively with high-dose corticosteroids and two others who had transient cough and dyspnea. The authors should be commended for successfully showing that this therapeutic regimen is tolerated in humans with significant disease burden.

Nonetheless, key questions about the engraftment and functionality of these cells remain unanswered. The authors propose the lack of disease progression as evidence of engraftment, although any impact of the therapy is difficult to ascertain, as lung function decline > 1 year after transplantation is compared to that from diagnosis to baseline, which is up to 3 years previously. Confounders of treatment effects include the potential impact of medications, including trimethoprim-sulfamethoxazole, which has been shown to decrease respiratory infections, valganciclovir, which can reduce replication of DNA viruses that have been implicated in the pathogenesis of IPF, and the role of the immunosuppression itself., In addition, azathioprine, which is linked to a greater risk of hospitalization and death, was discontinued in 4 of 16 patients prior to enrollment. These questions can only be rigorously answered with a randomized controlled design.

The biological plausibility, available preclinical evidence, and feasibility of bronchoscopic delivery make ATII cell transplantation an intriguing therapeutic modality. However, a major challenge to future clinical investigation, in addition to designing a trial with a reasonable placebo arm that demonstrates efficacy, will be establishing and monitoring cell engraftment. In other examples of heterologous cell transplantation, both innate and adaptive immune responses have limited the potential success despite the use of immunosuppressive therapy comparable to that used for solid organ transplantation. The posttransplantation development of human leukocyte antibodies, which was seen in 5 of 16 patients in this study, has been implicated in the failure of islet cell and hepatocyte transplantation., Development of alloimmunity may also have implications on future lung transplantation. Proof of ATII cell graft survival is essential to justify continuing potentially toxic immunosuppressive therapy and would be useful for determining the need for retransplantation. Given the absence of readily measurable biomarkers of engraftment—for example, reductions in bilirubin levels in hepatocyte transplantation—development and validation of novel surrogate measures would be instrumental. Scientific and clinical studies examining the functionality of transplanted ATII cells in surfactant production, paracrine modulation, and epithelial regeneration would also add validity. It is incumbent on the IPF community to perform thorough mechanistic and preclinical investigations, coupled with careful trial design, deserving of the personal investment of the patients who participate in these forms of clinical trials.

This study adds to a growing body of literature evaluating novel therapeutic agents based on the current understanding of disease mechanisms in patients with IPF. Although the path forward for ATII cell transplantation may be challenging, it may prove to be valuable in changing the disease trajectory, even in patients with prior severe disease or as an alternative to standard orthotopic lung transplantation. Given the complex pathobiological features of IPF, treatments will likely be used in combination with the ultimate goal of restoring normal alveolar structure and function. Recreating the epithelial lining may, in fact, prove to be a silver lining that has been long awaited.

References

Ahluwalia N. .Shea B.S. .Tager A.M. . New therapeutic targets in idiopathic pulmonary fibrosis. aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med. 2014;190:867-878 [PubMed]journal. [CrossRef] [PubMed]
 
Toonkel R. . Mesenchymal stem cells and idiopathic pulmonary fibrosis. potential for clinical testing. Am J Respir Crit Care Med. 2013;188:133-140 [PubMed]journal. [CrossRef] [PubMed]
 
Ortiz L.A. .Gambelli F. .McBride C. .et al Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407-8411 [PubMed]journal. [CrossRef] [PubMed]
 
Chambers D.C. .Enever D. .Ilic N. .et al A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19:1013-1018 [PubMed]journal. [CrossRef] [PubMed]
 
Tzouvelekis A. .Paspaliaris V. .Koliakos G. . A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171- [PubMed]journal. [CrossRef] [PubMed]
 
Salazar K.D. .Lankford S.M. .Brody A.R. . Mesenchymal stem cells produce wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;297:L1002-L1011 [PubMed]journal. [CrossRef] [PubMed]
 
Serrano-Mollar A. .Gay-Jordi G. .Guillamat-Prats R. . Safety and tolerability of alveolar type II cell transplantation in idiopathic pulmonary fibrosis. Chest. 2016;150:533-543 [PubMed]journal
 
Serrano-Mollar A. .Nacher M. .Gay-Jordi G. .Closa D. .Xaubet A. .Bulbena O. . Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis. Am J Respir Crit Care Med. 2007;176:1261-1268 [PubMed]journal. [CrossRef] [PubMed]
 
Shulgina L. .Cahn A.P. .Chilvers E.R. .et al Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial. Thorax. 2013;68:155-162 [PubMed]journal. [CrossRef] [PubMed]
 
Tang Y.W. .Johnson J.E. .Browning P.J. .et al Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol. 2003;41:2633-2640 [PubMed]journal. [CrossRef] [PubMed]
 
The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Hughes R.D. .Mitry R.R. .Dhawan A. . Current status of hepatocyte transplantation. Transplantation. 2012;93:342-347 [PubMed]journal. [CrossRef] [PubMed]
 
Piemonti L. .Everly M.J. .Maffi P. .et al Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes. 2013;62:1656-1664 [PubMed]journal. [CrossRef] [PubMed]
 

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References

Ahluwalia N. .Shea B.S. .Tager A.M. . New therapeutic targets in idiopathic pulmonary fibrosis. aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med. 2014;190:867-878 [PubMed]journal. [CrossRef] [PubMed]
 
Toonkel R. . Mesenchymal stem cells and idiopathic pulmonary fibrosis. potential for clinical testing. Am J Respir Crit Care Med. 2013;188:133-140 [PubMed]journal. [CrossRef] [PubMed]
 
Ortiz L.A. .Gambelli F. .McBride C. .et al Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407-8411 [PubMed]journal. [CrossRef] [PubMed]
 
Chambers D.C. .Enever D. .Ilic N. .et al A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19:1013-1018 [PubMed]journal. [CrossRef] [PubMed]
 
Tzouvelekis A. .Paspaliaris V. .Koliakos G. . A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171- [PubMed]journal. [CrossRef] [PubMed]
 
Salazar K.D. .Lankford S.M. .Brody A.R. . Mesenchymal stem cells produce wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;297:L1002-L1011 [PubMed]journal. [CrossRef] [PubMed]
 
Serrano-Mollar A. .Gay-Jordi G. .Guillamat-Prats R. . Safety and tolerability of alveolar type II cell transplantation in idiopathic pulmonary fibrosis. Chest. 2016;150:533-543 [PubMed]journal
 
Serrano-Mollar A. .Nacher M. .Gay-Jordi G. .Closa D. .Xaubet A. .Bulbena O. . Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis. Am J Respir Crit Care Med. 2007;176:1261-1268 [PubMed]journal. [CrossRef] [PubMed]
 
Shulgina L. .Cahn A.P. .Chilvers E.R. .et al Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial. Thorax. 2013;68:155-162 [PubMed]journal. [CrossRef] [PubMed]
 
Tang Y.W. .Johnson J.E. .Browning P.J. .et al Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol. 2003;41:2633-2640 [PubMed]journal. [CrossRef] [PubMed]
 
The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968-1977 [PubMed]journal. [CrossRef] [PubMed]
 
Hughes R.D. .Mitry R.R. .Dhawan A. . Current status of hepatocyte transplantation. Transplantation. 2012;93:342-347 [PubMed]journal. [CrossRef] [PubMed]
 
Piemonti L. .Everly M.J. .Maffi P. .et al Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes. 2013;62:1656-1664 [PubMed]journal. [CrossRef] [PubMed]
 
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