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In this month's issue, Greer et al. [1] present the results of a single center study assessing the clinical efficacy of extracorporeal photopheresis (ECP) treatment in lung transplant recipients with azithromycin-refractory, chronic lung allograft dysfunction (CLAD) and attempt to associate clinical response to several CLAD phenotypes. Despite the inherent limitations of an uncontrolled, retrospective analysis, and despite having a heterogeneous set of patients in terms of the level of bronchiolitis obliterans syndrome (BOS) / CLAD stage at the time ECP treatment was started, with the majority unfortunately being advanced, this study documents the efficacy of ECP in 54% of the treated population and identifies three subgroups (restrictive allograft syndrome, rapidly progressive and non-neutrophilic) of CLAD that were significantly less likely to benefit from ECP. Importantly, an actual survival advantage in the responder cohort was demonstrated, as opposed to merely documenting stabilization in pulmonary function testing in a nonpredictable percent of treated patients as in prior literature.

Since first receiving US Food and Drug Administration approval for the treatment of cutaneous T cell lymphoma (CTCL) in 1988, ECP has been utilized experimentally and clinically in a variety of disease states including chronic and acute graft-versus-host disease (GvHD) following allogeneic bone marrow transplantation, scleroderma, Crohn's disease, atopic dermatitis, lupus erythematosus, pemphigus, type 1 diabetes and other miscellaneous autoimmune diseases, in addition to solid organ transplantation [2]. It has been 14 years since a prospective randomized trial assessing the efficacy of ECP in the prevention of cardiac allograft rejection was published [3], and despite the failure of most conventional immunosuppressive agents to have any impact on the course of BOS which remains a far greater clinical problem than cardiac rejection in the current era, there has yet to be prospective trials with a true randomized control group to assess either an early stage BOS (0 p or 1) interventional trial with ECP or the prophylactic effect of ECP starting immediately after transplantation on the development of BOS, in which an immunomodulatory technique may have the potential for clinically meaningful effects. A long-standing logistical obstacle to this therapy's adoption has been the need for peripheral intravenous or often even central venous access and having to be “attached” to a machine-based technology. However, recent clinical trials, regulatory approval and subsequent use, albeit to a limited extent, of the intravenously administered CTLA-4Ig fusion protein Belatacept in renal transplantation does show the willingness of the transplant community to consider the use of an “inconvenient” maintenance agent if the risk/benefit ratio justifies the therapy.

As in the case of any therapy, whether it is a small molecule or a biologic, in which a beneficial effect precedes the establishment of mode of action, the strongly successful efficacy of ECP in CTCL significantly slowed the scientific progress of basic mechanistic research. Experimental models and human studies have demonstrated ECP associated modulation of dendritic cells, alteration of cytokine profiles and induction of specific Tcell subpopulations [4]. ECP induces psoralen-mediated DNA cross-linkages, results in apoptosis of lymphoid cells, including natural killer and Tcells. These apoptotic lymphocytes are phagocytosed and eliminated upon re-infusion by immature dendritic cells, which subsequently undergo maturation and present antigenic peptides. The ECP-initiated cellular mechanisms of differentiation are associated with alterations of a variety of cytokines including tumor necrosis factor, interleukin-6, transforming growth factor-beta and activation of CD36-positive macrophages. Depending on the experimental model or clinical disease state studied, ECP has demonstrated changes in Th1/Th2 balance with induction of anti-inflammatory cytokines and reduction in pro-inflammatory cytokines. It has been postulated that ECP causes an immunomodulatory rather than a general immunosuppressive state, possibly via the induction of Tregs. Tregs induced in this fashion express CD4, CD25 and FoxP3. Additionally, the release of IL-10 appears to be involved in this process. A clinical study in chronic GvHD measured serum B cell activating factor (BAFF) and found that BAFF levels post-ECP predicted response. Manifestation of acute GvHD in patients can be associated with a low number of Tregs, and induction of T cells with regulatory properties following ECP has been confirmed in both murine GvHD models and in preliminary human studies. Lastly, studies have found that ECP can increase or stabilize the number of peripheral Treg counts in lung transplant recipients who showed functional stabilization. The potential role of regulatory cells as well as antigen presenting cells and non-Tregs associated with regulatory cytokine production capabilities has become increasingly prominent through a growing body of literature in the field of lung transplantation in experimental models, in vitro assays and preliminary human studies [5].

Unfortunately, this study was not designed to assess the mechanistic aspects or potential biomarkers that could potentially be associated with a therapeutic ECP effect by evaluating either cell populations or cytokines in peripheral blood or bronchoalveolar lavage fluid. Such associated mechanistic research in the context of differential clinical effects will be required in order to help guide dosimetry and frequency of ECP and the need for such therapy to be intensified or when it is safe to be minimized or stopped. Regardless, this study lends significant credibility to the strategy of moving ECP from its current role as a third or fourth line rescue therapy for BOS or CLAD to evaluating it in a randomized clinical trial setting as an early first or second line therapeutic approach. To really improve outcomes in lung transplantation, as opposed to many other things in life, “better late than never” should no longer be the operational paradigm.

Disclosure

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The author of this manuscript has a conflict of interest to disclose as described by the American Journal of Transplantation. M.L.B. had a scientific speaker agreement during 2012 with Johnson & Johnson.

References

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