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Are Tregs the ONE for Lung Transplantation?


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Rebecca Shilling, MD
University of Illinois College of Medicine at Chicago
Chicago, IL, USA
shilling@uic.edu



The balance between infection and immunosuppression is never trickier than with the organ responsible for filtering the air we breathe and for oxygenating the body. Is it possible to flip the balance back to homeostasis and away from constant immune suppression? The normal immune homeostasis of the lung involves multiple regulatory mechanisms, from multiple cell types that are only beginning to be understood [1]. One major mechanism is CD4+ T regulatory cells (Tregs), characterized by expression of the transcription factor Foxp3 [2-4]. Tregs are able to prevent activation of other T cells and are necessary to avoid autoimmunity [1]. They are known to prevent, or delay rejection in solid organ transplant models and have been associated with improved outcomes after human lung transplant ([5,6]; nicely reviewed in [7]). Data from mouse models also suggest Tregs may be beneficial for inducing tolerance to lung allografts [8,9]. Could they be used as therapy for human transplant recipients? The ONE Study (www.onestudy.org), funded by the European Commission's Seventh Framework, hopes to start answering this important question [10].

Foxp3+ Tregs can be broken down into two major groups and include natural Tregs (thymic-derived) and induced Tregs (iTregs, produced in the periphery). Both subsets can suppress other T cells, although the mechanisms in vivo are not entirely clear. The "suppressor cell" concept is not new to immunology, and was first proposed by Gershon and Kondo in 1971 and was established in transplant by Kilshaw in 1975 (reviewed in [11]). Suppressor cells generally fell out of favor until the mid-80's, when their importance was reasserted in transplantation and in the prevention of autoimmunity [11]. Waldmann and colleagues established that tolerance to allografts could be transferred and "infectious," as regulatory CD4+ T cells could recruit other T cells to promote allograft tolerance [12]. Subsequently, the transcription factor Foxp3 was established as necessary for the development and function of Tregs [2-4]. Since the affirmation that suppressor cells were real and potent regulators of the immune response, the challenge has been to harness the power of Tregs for human therapy.

The number of Tregs naturally occurring in humans is a small percentage of the total T cell repertoire. Thus the focus has been on ex vivo expansion of either natural or induced Tregs [11]. Multiple regimens have been reported, but the challenge has been to expand a stable suppressive population [11,13,14]. Especially with natural Tregs, which are mostly specific for self-antigens, loss of Foxp3 expression and the possibility of being reactive and dangerous to self is a real concern. For this reason, iTregs, which are not thought to be self-reactive, may be an important alternative (for a more thorough discussion ref. [14]). In addition to maintaining stability, the numbers needed to treat for efficacy are not insignificant and require substantial expansion in the laboratory [11,13]. There are also good data that while Tregs are globally suppressive, they are more potent when they are antigen-specific [13]. Donor-specific expanded Tregs would be preferable, but this is obviously a challenge for cadaveric donors, such as in lung transplant. Further, the mechanisms by which Tregs function in vivo are not completely understood and the location where they function, either in the graft or lymphoid tissue, is also unknown. Thus, there are many challenges to overcome before Tregs are widely available for therapy, not the least of which, are the GMP compliant protocols required to generate cellular therapy for clinical use [14].

Nevertheless, the promise of using suppressor cell therapy for allotransplantation is getting more and more real. Early phase clinical trials of human Treg therapy to treat graft versus host disease (GVHD) or Type I diabetes have been reported [11]. Even more exciting, the ONE study has begun in eight sites in Europe and in the U.S. [10]. The ONE study is a multicenter Phase 1/11a trial evaluating the safety and feasibility of transferring Treg, compared to seven different regulatory cell based therapies, in living donor kidney transplant recipients [10,11]. The aim is to have results by 2016 to smartly choose the most feasible and safe cell therapy for a larger trial to determine efficacy. This is not long to get a hint of whether the promise of 40+ years of basic research on suppressor cells will be realized. While the lung will be a considerable challenge for Treg therapy, the relative magnitude of immunosuppression required, compared to other solid organs, such as kidney and liver, suggest the potential benefits could be even greater. Let's hope for some good regulation to arrive in a timely fashion for lung transplantation. ■

Disclosure Statement: The author has no conflicts to disclose.


References:

  1. Wood KJ, Bushell A, Hester J (2012) Regulatory immune cells in transplantation. Nat Rev Immunol 12: 417-430.
  2. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330-336.
  3. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-1061.
  4. Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4: 337-342.
  5. Bhorade SM, Chen H, Molinero L, Liao C, Garrity ER, et al. (2010) Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation 90: 540-546.
  6. Nakagiri T, Warnecke G, Avsar M, Thissen S, Kruse B, et al. (2012) Lung function early after lung transplantation is correlated with the frequency of regulatory T cells. Surg Today 42: 250-258.
  7. Neujahr DC, Larsen CP (2011) Regulatory T cells in lung transplantation--an emerging concept. Semin Immunopathol 33: 117-127.
  8. Dodd-o JM, Lendermon EA, Miller HL, Zhong Q, John ER, et al. (2011) CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant. Am J Transplant 11: 1815-1824.
  9. Li W, Bribriesco AC, Nava RG, Brescia AA, Ibricevic A, et al. (2012) Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis. Mucosal Immunol 5: 544-554.
  10. Geissler EK (2012) The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. Transplant Res 1: 11.
  11. Juvet SC, Whatcott AG, Bushell AR, Wood KJ (2014) Harnessing regulatory T cells for clinical use in transplantation: the end of the beginning. Am J Transplant 14: 750-763.
  12. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, et al. (1993) "Infectious" transplantation tolerance. Science 259: 974-977.
  13. Tang Q, Bluestone JA (2013) Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med 3.
  14. Waldmann H, Hilbrands R, Howie D, Cobbold S (2014) Harnessing FOXP3+ regulatory T cells for transplantation tolerance. J Clin Invest 124: 1439-1445.



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