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Research Highlights

Fadi, Issa, DPhil, FRCS(Plast)1

doi: 10.1097/TP.0000000000002550
In View: Research Highlights

1 Nuffield Department of Surgical Sciences, University ofOxford, John Radcliffe Hospital, Oxford, United Kingdom.

Received 12 November 2018. Revision received 15 November 2018.

Accepted 15 November 2018.

The author declares no conflicts of interest.

Correspondence: Fadi Issa, PhD, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. (fadi.issa@nds.ox.ac.uk).

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Allogeneic BK Virus-specific T Cells for Progressive Multifocal Leukoencephalopathy

Muftuoglu M, Olson A, Marin D, et al. N Engl J Med. 2018;379:1443-1451.

Over a dozen polyoma viruses have been identified in humans, with approximately 75% of the adult population being latently infected with BK virus (BKV) in the urothelium. Although immunocompetent patients are generally asymptomatic, in immunosuppressed transplant recipients of solid organ transplants, the infection may result in nephropathy due to the reactivation of the virus in the graft; hematopoietic stem cell (HSC) transplant recipients may develop a hemorrhagic cystitis.1 Treatment of BKV is complicated because it requires a reduction in immunosuppression, which is not possible in HSC transplant recipients who are inherently immunosuppressed as part of their preconditioning regimen. To address this unmet clinical need, there has been increasing interest in the use of virus-specific T cells for the treatment of BK virus hemorrhagic cystitis, with one group reporting encouraging results in 16 HSC transplant recipients.2 Another latent polyomavirus, JC virus (JCV), can result in a frequently fatal demyelinating progressive multifocal leukoencephalopathy (PML) in a very small number of transplant recipients. There are no satisfactory effective treatments for PML. Importantly, BKV and JCV share a significant degree of structural homology, meaning that T cells specific for BKV antigens can also target JCV. Capitalizing on this feature, Muftuoglu and colleagues have reported on the use of third party–derived ex vivo–expanded BK virus-specific cytotoxic T lymphocyte (CTL) cellular therapy in 2 patients who developed PML after an HSC transplant.3 In the full report published in the New England Journal of Medicine, the investigators report on their experience using this CTL product to treat 3 patients with PML.4 BKV-specific CTL products were generated from 27 healthy donors and cryopreserved for later use. The most closely HLA-matched T cell line was then selected for each treated patient and cells administered at a dose of 2 × 105/kg. An advantage of the partial HLA mismatch of the cell product was the ability to track it in vivo by flow cytometry using HLA-specific antibodies. This approach was assessed in 1 patient with approximately 20% of T cells in the cerebrospinal fluid (CSF) being of donor cellular therapy origin. Most importantly, after infusion, all 3 patients demonstrated a reduction in JCV load in the CSF with a marked clinical improvement. After further infusions of CTL therapy in the first patient, there was a complete clearance of JCV in the CSF and a resolution of clinical findings over a 2-year follow-up. Although a reduction in JCV load was observed in the second patient after a further CTL infusion, the symptoms of PML did not improve and the patient died 8 months after commencing CTL treatment. In the third patient, additional CTL infusions led to a complete clearance of CSF JCV with the patient regaining independent mobility.

This study demonstrates the promise of cellular therapy in cases where current treatment modalities are unsatisfactory. There are inherent practical advantages to the use of third party–derived cellular therapies where the product may be banked for future use and HLA matching as required. Whether this is also possible for patients receiving solid organ transplants in whom the host immune system is not as profoundly suppressed will be of interest.

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REFERENCES

  1. Lamarche C, Orio J, Collette S, et al. BK polyomavirus and the transplanted kidney: immunopathology and therapeutic approaches. Transplantation. 2016;100:2276–2287.
  2. Tzannou I, Papadopoulou A, Naik S, et al. Off-the-shelf virus-specific Tcells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2017;35:3547–3557.
  3. Muftuoglu M, Ahmed S, Olson A, et al. Use of expanded allogeneic third party BK virus specific cytotoxic t cells to target progressive multifocal Leukoencephalopathy (Abstract from the 56th ASH meeting, 2016). Blood. 2016;128:3365.
  4. MuftuogluM, Olson A,Marin D, et al. Allogeneic BK virus-specific Tcells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379: 1443–1451.
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Cell Surface Polysaccharides of Bifidobacterium bifidum Induce the Generation of Foxp3+ Regulatory T Cells

Verma R, Lee C, Jeun EJ, et al. Sci Immunol. 2018;3(28).

The term “microbiome” refers to the combination of commensal organisms (ie, microbiota) together with their byproducts. Several factors may impact the makeup of the microbiome after transplantation and result in dysbiosis, including the use of immunosuppressants, antibiotics, antivirals, and chemotherapy. Although present on a number of mucosal and epithelial surfaces, the term “micriobiome” is commonly associated with the gastrointestinal tract where there is a high diversity and number of microbiota. These organisms contribute to several homeostatic processes with the ability to modulate both local and systemic immune responses. The microbiome has a role in T cell development and maturation, for example, through the promotion of specific T helper subset differentiation. Of interest in transplantation are the observations that the microbiome may alter the outcome of transplant alloresponses.1 However, the microbiome is a complex ecosystem with different microbial strains having distinct influences on immunity.2 There are previous reports that some commensals have a positive effect on regulatory T (Treg) cell differentiation and function, although the precise mechanisms underlying this are not clear.3 These reports offer a therapeutic opportunity to promote certain microbiota through the introduction of specific probiotics. In the study from Verma and coworkers, a collection of probiotic strains were screened ex vivo for their Treg cell-promoting abilities.4 Here, the authors show that monocolonization of germ-free mice with a strain of Bifidobacterium bifidum (Bb) promotes the development of Treg cells. Mechanisms involved include the generation of regulatory dendritic cells by Bb cell surface β-glucan/galactan polysaccharides. The Treg cells that develop in response have a broad specificity for both dietary antigens, commensal microbiota in addition to Bb and can suppress intestinal inflammation.

These data are of interest given previous reports of germ-free or antibiotic-treated mice displaying prolonged allograft survival through a mechanism that includes reduced-type I IFN signaling in antigen-presenting cells.5 Understanding how to harness these potentially beneficial effects in transplant recipients is expected to be an important area for future investigation.

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REFERENCES

  1. Tabibian JH, Kenderian SS. The microbiome and immune regulation after transplantation. Transplantation. 2017;101:56–62.
  2. Yang Y, Torchinsky MB, Gobert M, et al. Focused specificity of intestinal TH17 cells toward commensal bacterial antigens. Nature. 2014;510: 152–156.
  3. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500: 232–236.
  4. Verma R, Lee C, Jeun EJ, et al. Cell surface polysaccharides of Bifidobacterium bifidum induce the generation of Foxp3+ regulatory T cells. Sci Immunol. 2018;3.
  5. Lei YM, Chen L, Wang Y, et al. The composition of the microbiota modulates allograft rejection. J Clin Invest. 2016;126:2736–2744.
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