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The relevance of photopheresis to autoreactive diseases
Clinical Immunology (2012) 142, 97–100 available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
The relevance of photopheresis to autoreactive diseases Extracorporeal photopheresis (ECP) was initially approved by the United States Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL) in 1988. Since then, its application has expanded to encompass patients with graft versus host disease (GVHD), solid organ transplant rejection, and autoimmunity. It is currently used in over 300 locations worldwide with over 700,000 treatments administered for patients with CTCL alone. The efficacy, excellent safety profile and relative ease of use of ECP have contributed to the growing enthusiasm for this therapy. In this issue of the Journal, Papp et al. elegantly demonstrate the clinical and immunomodulatory effects of ECP in patients with systemic sclerosis. It has been nearly two decades since the initial controlled trial of ECP suggesting potential benefit for systemic sclerosis was published [1]. This multicenter trial enrolled seventy-nine patients with recent onset systemic sclerosis to receive monthly ECP versus the control therapy D-penicillamine. Individuals who received ECP showed improvement in their mean skin severity score, mean percent skin involvement and mean oral aperture measurements as compared to progression of disease manifestations among patients in the D-penicillamine arm. Importantly, a concomitant decrease in dermal thickness was observed in skin biopsies among study subjects with clinical improvement [1]. A follow-up double-blinded sham controlled randomized trial was reported by Knobler et al. in 2006 which similarly demonstrated improvement in skin and joint involvement in the active treatment arm [2]. This finding was later supported by work performed by Reich et al. in 2007 [3]. While the breadth of its clinical applications increases, the understanding of the precise mechanisms of action of ECP are just beginning to emerge. It was originally demonstrated by Yoo and colleagues that exposure of treated lymphoid cells in the photopheresis device to 8-methoxypsoralin (8-MOP) and ultraviolet A (UVA) irradiation could lead to a high rate of apoptosis of the treated cells [4,5]. The treated peripheral blood cells are then readministered to the patients upon conclusion of therapy. Presumably, the proapoptotic effects could eliminate a significant population of pathogenic cells, particularly since large, activated T-cells 1521-6616/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2011.11.003
appear to be most susceptible to the combined effects of 8-MOP and UVA exposure. However, it is noteworthy that during an ECP procedure, only 2-5% of the total body mononuclear cell (PBMCs) compartment is exposed, implying that other immunologic mechanisms are playing a role. It was long presumed that the substantial numbers of apoptotic cells generated during photopheresis could be processed by antigen presenting cells when returned to the patient upon conclusion of therapy, thereby leading to an anticlonotypic immune response. Indeed, Albert e. al. was among the first to demonstrate dendritic cell processing of antigens from apoptotic cells with the subsequent induction of anticlonotypic cytolytic T-cells [6]. More recent studies in animal models have confirmed that ECP can induce antigenspecific regulatory T-cells without concomitant suppression of third party antigen immune responsiveness against expanded populations of pathogenic T-cells [7]. It is now apparent that ECP has the capacity to promote a tolerogenic state through the induction of CD4+ CD25+ FoxP3+ T regulatory cells [8–10]. In addition, monocytes have an increased capacity to secrete IL-10 [11] also implying a role for Tr1 cells. Finally, PBMCs may also increase IFN-gamma and decrease IL-4 production [12]. Regulatory T-cells play a key role in maintaining immune tolerance. The earliest experiments looking at thymectomized mice revealed the development of organ specific autoimmune disease [13]. This phenomenon could be prevented or reversed by adding back FoxP3 expressing regulatory T-cells [14,15]. As a result, alterations in these Treg populations, as described by Papp et al. play an important role in the development of autoimmunity and promoting their induction, survival and function can greatly contribute to the outcome of these patient populations. The patients described by Papp and colleagues, experienced a marked reduction in dermal thickness and improvement in joint mobility while internal organ involvement remained stable. They describe a shift in T-cell populations with an increase in Tr1 and Treg cells as early as after the second round of treatment with ECP, with a concomitant decrease in Th17 cells. Additionally, they describe a shift from pro- to anti-inflammatory and anti-fibrotic cytokines with an increase in IL-10, IL-1Ra, HGF and a decrease in TGF-beta
98 and CCL2, respectively. They observed a direct positive correlation in the reduction of a pro-inflammatory cell population, Th17, and skin thickness. The role of ECP has also been evaluated in other autoimmune disease states including pemphigus vulgaris [16], systemic lupus erythematosus [17] and rheumatoid arthritis [18]. While promising, the results in these diseases are based on smaller scale studies. Treatment with ECP has become quite relevant to other “autoreactive” disorders that may also benefit from an enhanced Treg cell response including GVHD and solid organ transplantation rejection. Conversely, in the case of CTCL, it might seem paradoxical that a treatment which produces Tregs could be useful for a malignancy, particularly when patients with the most intact host immune response and lowest circulating tumor burden appear to have the highest response rates. It has been postulated by some that Tregs may actually inhibit the proliferation of malignant CD4+ Tcells. Studies have shown that patients with early stage disease have an increased number of FoxP3+ T-cells in the skin in comparison to those with advanced tumor stage or large cell transformation [19,20]. Treatment with ECP may actually increase and strengthen the Treg population contributing to its ultimate success [21]. With regard to the transplantation setting, Perez and colleagues, first described the ability of ECP to tolerize an animal to a skin allograft. They were able to demonstrate an attenuated response to alloantigens both in vivo and in vitro in mice whose splenocytes were photoinactivated by UVA and 8-MOP [22]. A subsequent controlled trial by Barr et al., demonstrated a significant decrease in acute cardiac rejection and in CMV infection among patients who had ECP added to a standard triple immunosuppressive regimen as compared to patients not receiving ECP [23]. A proposed mechanism is through the generation of tolerogenic dendritic cells and an increase in number of regulatory T-cells with a suppressive phenotype [24]. Similarly, ECP is used in the setting of grade I and II acute GVHD [25,26] as well as chronic GVHD [27]. It is thought that the induction of Tregs allows for suppression of the vigorous donor response [21]. Finally, in murine models of contact hypersensitivity, ECP through the generation of IL-10 and induction of regulatory T-cells acts to inhibit the effector phase and sensitization of contact hypersensitivity [10].
How can we enhance the immunomodulatory effects of ECP? As our understanding of the immunomodulatory effects of ECP continues to expand, we have become more adept in adding supplementary therapeutic agents to enhance those effects. A key example is in the management of patients with CTCL. Rook et al., in as early as 1991, reported the beneficial effect of adding low dose interferon (IFN) alpha to ECP for patients with advanced CTCL [28]. Subsequent studies have confirmed that a multimodality approach to the management of CTCL patients, including immune augmentatory cytokines such as IFN-alpha and IFN-gamma, are associated with improved outcomes [29,30]. Similarly, the addition of immune modifying agents to ECP may provide significant benefit in managing patients with systemic sclerosis and other inflammatory conditions.
Editorial Sirolimus (Rapamycin), an mTOR inhibiter, can inhibit the differentiation of naïve T-cells to Th17 cells [31] and promote the generation and survival of Treg cells [32,33]. In addition, sirolimus has enhanced anti-fibrotic effects in mouse models of systemic sclerosis as well as other fibrotic disease states [34,35]. Vorinostat (Zolinza) is a histone deacetylase (HDAC) inhibitor approved for use in CTCL. Evidence has demonstrated further benefit of HDAC inhibitors through their ability to enhance the production and suppressive function of Foxp3+ Treg cells [36]. The combination of sirolimus and an HDAC inhibitor may lead to complete tolerance to an allograft in animal models. Bortezomib (Velcade) is a proteasome inhibitor used to treat multiple myeloma. Recent evidence has demonstrated that through inhibition of TGF-beta1 gene expression, Bortezomib can prevent both lung and skin fibrosis induced by bleomycin in mice [37]. Capitalizing on the anti-fibrotic effects of these medications in conjunction with ECP may prove beneficial in managing patients with systemic sclerosis and sclerodermatous chronic GVHD. Many of the immunosuppressive agents used today act by nonspecific global immunosuppression rendering a host at increased risk for opportunistic infections, development of malignant tumors, as well as other adverse effects. Aside from reports of transient hypotension and rarely, low-grade fevers and problems related to poor vascular access, ECP tends to be particularly well tolerated [25]. Most importantly, it does not place patients at increased risk for opportunistic infections and it allows for a dose reduction of a patient's immunosuppressive regimen. However, contraindications include severe cardiac or renal impairment, hypersensitivity to psoralen and certain coagulation disorders. In the future, the use of photopheresis might be superseded or complemented by methods aimed at directly infusing expanded populations of Tregs. Brunstein et al. established a method by which CD4+ CD25+ FoxP3+ T regulatory cells can be enriched from umbilical cord blood and injected back to the patient [38]. They demonstrated a reduction in the incidence of grade II-IV acute GVHD without significant associated comorbidity. This would provide a novel mechanism to boost the host's systemic immunoregulatory response. The article by Papp et al. does an excellent job in defining the immunologic profile of patients with systemic sclerosis undergoing treatment with ECP and its potential benefits. Future goals should be directed at the precise elucidation of the full mechanisms of action of ECP so that this treatment can be optimally harnessed for the full spectrum of responsive conditions.
References [1] A.H. Rook, B. Freundlich, B.V. Jegasothy, M.I. Perez, W.G. Barr, S.A. Jimenez, R.L. Rietschel, B. Wintroub, M.B. Kahaleh, J. Varga, et al., Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial, Arch. Dermatol. 128 (1992) 337–346. [2] R.M. Knobler, L.E. French, Y. Kim, E. Bisaccia, W. Graninger, H. Nahavandi, F.J. Strobl, E. Keystone, M. Mehlmauer, A.H. Rook, I. Braverman, A randomized, double-blind, placebo-
Editorial controlled trial of photopheresis in systemic sclerosis, J. Am. Acad. Dermatol. 54 (2006) 793–799. [3] S. Reich, T. Gambichler, P. Altmeyer, A. Kreuter, Extracorporeal photopheresis in systemic sclerosis: effects on organ involvement? J. Am. Acad. Dermatol. 56 (2007) 348–349. [4] A.H. Rook, K.R. Suchin, D.M. Kao, E.K. Yoo, W.H. Macey, B.J. DeNardo, P.G. Bromely, Y. Geng, J.M. Junkins-Hopkins, S.R. Lessin, Photopheresis: clinical applications and mechanism of action, J. Investig. Dermatol. Symp. Proc. 4 (1999) 85–90. [5] E.K. Yoo, A.H. Rook, R. Elenitsas, F.P. Gasparro, B.R. Vowels, Apoptosis induction of ultraviolet light A and photochemotherapy in cutaneous T-cell Lymphoma: relevance to mechanism of therapeutic action, J. Invest. Dermatol. 107 (1996) 235–242. [6] M.L. Albert, B. Sauter, N. Bhardwaj, Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs, Nature 392 (1998) 86–89. [7] A. Maeda, A. Schwarz, K. Kernebeck, N. Gross, Y. Aragane, D. Peritt, T. Schwarz, Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells, J. Immunol. 174 (2005) 5968–5976. [8] E. Biagi, I. Di Biaso, V. Leoni, G. Gaipa, V. Rossi, C. Bugarin, G. Renoldi, M. Parma, A. Balduzzi, P. Perseghin, A. Biondi, Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4+CD25+GITR+Foxp3+CD62L+ functional regulatory T-cells in patients with graft-versus-host disease, Transplantation 84 (2007) 31–39. [9] E. Gatza, C.E. Rogers, S.G. Clouthier, K.P. Lowler, I. Tawara, C. Liu, P. Reddy, J.L. Ferrara, Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells, Blood 112 (2008) 1515–1521. [10] A. Maeda, A. Schwarz, A. Bullinger, A. Morita, D. Peritt, T. Schwarz, Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity via two mechanisms: generation of IL-10 and induction of regulatory T cells, J. Immunol. 181 (2008) 5956–5962. [11] M. Di Renzo, P. Sbano, G. De Aloe, A.L. Pasqui, P. Rubegni, A. Ghezzi, A. Auteri, M. Fimiani, Extracorporeal photopheresis affects co-stimulatory molecule expression and interleukin-10 production by dendritic cells in graft-versus-host disease patients, Clin. Exp. Immunol. 151 (2008) 407–413. [12] M. Di Renzo, P. Rubegni, G. De Aloe, L. Paulesu, A.L. Pasqui, L. Andreassi, A. Auteri, M. Fimiani, Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma, Immunology 92 (1997) 99–103. [13] Y. Nishizuka, T. Sakakura, Thymus and reproduction: sexlinked dysgenesia of the gonad after neonatal thymectomy in mice, Science 166 (1969) 753–755. [14] S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, M. Toda, Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J. Immunol. 155 (1995) 1151–1164. [15] S. Sakaguchi, N. Sakaguchi, J. Shimizu, S. Yamazaki, T. Sakihama, M. Itoh, Y. Kuniyasu, T. Nomura, M. Toda, T. Takahashi, Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance, Immunol. Rev. 182 (2001) 18–32. [16] A.H. Rook, B.V. Jegasothy, P. Heald, G.T. Nahass, C. Ditre, W.K. Witmer, G.S. Lazarus, R.L. Edelson, Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris, Ann. Intern. Med. 112 (1990) 303–305.
99 [17] R.M. Knobler, W. Graninger, A. Lindmaier, F. Trautinger, J.S. Smolen, Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Arthritis Rheum. 35 (1992) 319–324. [18] S.E. Malawista, D.H. Trock, R.L. Edelson, Treatment of rheumatoid arthritis by extracorporeal photochemotherapy. A pilot study, Arthritis Rheum. 34 (1991) 646–654. [19] L.M. Gjerdrum, A. Woetmann, N. Odum, C.M. Burton, K. Rossen, G.L. Skovgaard, L.P. Ryder, E. Ralfkiaer, FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival, Leukemia 21 (2007) 2512–2518. [20] M.M. Tiemessen, T.J. Mitchell, L. Hendry, S.J. Whittaker, L.S. Taams, S. John, Lack of suppressive CD4+CD25+FOXP3+ T cells in advanced stages of primary cutaneous T-cell lymphoma, J. Invest. Dermatol. 126 (2006) 2217–2223. [21] V. Rao, M. Saunes, S. Jorstad, T. Moen, Cutaneous T cell lymphoma and graft-versus-host disease: a comparison of in vivo effects of extracorporeal photochemotherapy on Foxp3+ regulatory T cells, Clin. Immunol. 133 (2009) 303–313. [22] M. Perez, R. Edelson, L. Laroche, C. Berger, Inhibition of antiskin allograft immunity by infusions with syngeneic photoinactivated effector lymphocytes, J. Invest. Dermatol. 92 (1989) 669–676. [23] M.L. Barr, B.M. Meiser, H.J. Eisen, R.F. Roberts, U. Livi, R. Dall'Amico, R. Dorent, J.G. Rogers, B. Radovancevic, D.O. Taylor, V. Jeevanandam, C.C. Marboe, Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group, N. Engl. J. Med. 339 (1998) 1744–1751. [24] A. Lamioni, F. Parisi, G. Isacchi, E. Giorda, S. Di Cesare, A. Landolfo, F. Cenci, G.F. Bottazzo, R. Carsetti, The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo, Transplantation 79 (2005) 846–850. [25] K.E. McKenna, S. Whittaker, L.E. Rhodes, P. Taylor, J. Lloyd, S. Ibbotson, R. Russell-Jones, Evidence-based practice of photopheresis 1987–2001: a report of a workshop of the British Photodermatology Group and the U.K. Skin Lymphoma Group, Br. J. Dermatol. 154 (2006) 7–20. [26] S.R. Marshall, Technology insight: ECP for the treatment of GvHD–can we offer selective immune control without generalized immunosuppression? Nat. Clin. Pract. Oncol. 3 (2006) 302–314. [27] M.E. Flowers, J.F. Apperley, K. van Besien, A. Elmaagacli, A. Grigg, V. Reddy, A. Bacigalupo, H.J. Kolb, L. Bouzas, M. Michallet, H.M. Prince, R. Knobler, D. Parenti, J. Gallo, H.T. Greinix, A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease, Blood 112 (2008) 2667–2674. [28] A.H. Rook, M.B. Prystowsky, M. Cassin, M. Boufal, S.R. Lessin, Combined therapy for Sezary syndrome with extracorporeal photochemotherapy and low-dose interferon alfa therapy. Clinical, molecular, and immunologic observations, Arch. Dermatol. 127 (1991) 1535–1540. [29] K.R. Suchin, A.J. Cucchiara, S.L. Gottleib, J.T. Wolfe, B.J. DeNardo, W.H. Macey, P.G. Bromley, C.C. Vittorio, A.H. Rook, Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution, Arch. Dermatol. 138 (2002) 1054–1060. [30] B.A. Raphael, D.B. Shin, K.R. Suchin, K.A. Morrissey, C.C. Vittorio, E.J. Kim, J.M. Gardner, K.G. Evans, C.E. Introcaso, S.S. Samimi, J.M. Gelfand, A.H. Rook, High Clinical Response Rate of Sezary Syndrome to Immunomodulatory Therapies: Prognostic Markers of Response. Arch. Dermatol. (2011) [Epub ahead of print].
100 [31] H. Kopf, G.M. de la Rosa, O.M. Howard, X. Chen, Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells, Int. Immunopharmacol. 7 (2007) 1819–1824. [32] Y. Qu, B. Zhang, L. Zhao, G. Liu, H. Ma, E. Rao, C. Zeng, Y. Zhao, The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice, Transpl. Immunol. 17 (2007) 153–161. [33] L. Strauss, T.L. Whiteside, A. Knights, C. Bergmann, A. Knuth, A. Zippelius, Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin, J. Immunol. 178 (2007) 320–329. [34] A. Yoshizaki, K. Yanaba, Y. Iwata, K. Komura, F. Ogawa, M. Takenaka, K. Shimizu, Y. Asano, M. Hasegawa, M. Fujimoto, S. Sato, Treatment with rapamycin prevents fibrosis in tightskin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 62 (2010) 2476–2487. [35] E. Patsenker, V. Schneider, M. Ledermann, H. Saegesser, C. Dorn, C. Hellerbrand, F. Stickel, Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis. J. Hepatol. 55 (2011) 388–398. [36] L. Wang, E.F. de Zoeten, M.I. Greene, W.W. Hancock, Immunomodulatory effects of deacetylase inhibitors: therapeutic
Editorial targeting of FOXP3+ regulatory T cells, Nat. Rev. Drug Discov. 8 (2009) 969–981. [37] G.M. Mutlu, G.R. Budinger, M. Wu, A.P. Lam, A. Zirk, S. Rivera, D. Urich, S.E. Chiarella, L.H. Go, A.K. Ghosh, M. Selman, A. Pardo, J. Varga, D.W. Kamp, N.S. Chandel, J.I. Sznajder, M. Jain, Proteasomal inhibition after injury prevents fibrosis by modulating TGF-{beta}1 signalling. Thorax. [38] C.G. Brunstein, J.S. Miller, Q. Cao, D.H. McKenna, K.L. Hippen, J. Curtsinger, T. Defor, B.L. Levine, C.H. June, P. Rubinstein, P.B. McGlave, B.R. Blazar, J.E. Wagner, Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117 (2011) 1061–1070.
Sara Samimi, M.D. Alain H. Rook, M.D.⁎ Department of Dermatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA ⁎ Corresponding author at: One Convention Avenue, Department of Dermatology, 14 Penn Tower, Philadelphia, PA, USA. Fax:+1 215 615 4966. E-mail address: [email protected] (A.H. Rook).
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
The relevance of photopheresis to autoreactive diseases Extracorporeal photopheresis (ECP) was initially approved by the United States Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL) in 1988. Since then, its application has expanded to encompass patients with graft versus host disease (GVHD), solid organ transplant rejection, and autoimmunity. It is currently used in over 300 locations worldwide with over 700,000 treatments administered for patients with CTCL alone. The efficacy, excellent safety profile and relative ease of use of ECP have contributed to the growing enthusiasm for this therapy. In this issue of the Journal, Papp et al. elegantly demonstrate the clinical and immunomodulatory effects of ECP in patients with systemic sclerosis. It has been nearly two decades since the initial controlled trial of ECP suggesting potential benefit for systemic sclerosis was published [1]. This multicenter trial enrolled seventy-nine patients with recent onset systemic sclerosis to receive monthly ECP versus the control therapy D-penicillamine. Individuals who received ECP showed improvement in their mean skin severity score, mean percent skin involvement and mean oral aperture measurements as compared to progression of disease manifestations among patients in the D-penicillamine arm. Importantly, a concomitant decrease in dermal thickness was observed in skin biopsies among study subjects with clinical improvement [1]. A follow-up double-blinded sham controlled randomized trial was reported by Knobler et al. in 2006 which similarly demonstrated improvement in skin and joint involvement in the active treatment arm [2]. This finding was later supported by work performed by Reich et al. in 2007 [3]. While the breadth of its clinical applications increases, the understanding of the precise mechanisms of action of ECP are just beginning to emerge. It was originally demonstrated by Yoo and colleagues that exposure of treated lymphoid cells in the photopheresis device to 8-methoxypsoralin (8-MOP) and ultraviolet A (UVA) irradiation could lead to a high rate of apoptosis of the treated cells [4,5]. The treated peripheral blood cells are then readministered to the patients upon conclusion of therapy. Presumably, the proapoptotic effects could eliminate a significant population of pathogenic cells, particularly since large, activated T-cells 1521-6616/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2011.11.003
appear to be most susceptible to the combined effects of 8-MOP and UVA exposure. However, it is noteworthy that during an ECP procedure, only 2-5% of the total body mononuclear cell (PBMCs) compartment is exposed, implying that other immunologic mechanisms are playing a role. It was long presumed that the substantial numbers of apoptotic cells generated during photopheresis could be processed by antigen presenting cells when returned to the patient upon conclusion of therapy, thereby leading to an anticlonotypic immune response. Indeed, Albert e. al. was among the first to demonstrate dendritic cell processing of antigens from apoptotic cells with the subsequent induction of anticlonotypic cytolytic T-cells [6]. More recent studies in animal models have confirmed that ECP can induce antigenspecific regulatory T-cells without concomitant suppression of third party antigen immune responsiveness against expanded populations of pathogenic T-cells [7]. It is now apparent that ECP has the capacity to promote a tolerogenic state through the induction of CD4+ CD25+ FoxP3+ T regulatory cells [8–10]. In addition, monocytes have an increased capacity to secrete IL-10 [11] also implying a role for Tr1 cells. Finally, PBMCs may also increase IFN-gamma and decrease IL-4 production [12]. Regulatory T-cells play a key role in maintaining immune tolerance. The earliest experiments looking at thymectomized mice revealed the development of organ specific autoimmune disease [13]. This phenomenon could be prevented or reversed by adding back FoxP3 expressing regulatory T-cells [14,15]. As a result, alterations in these Treg populations, as described by Papp et al. play an important role in the development of autoimmunity and promoting their induction, survival and function can greatly contribute to the outcome of these patient populations. The patients described by Papp and colleagues, experienced a marked reduction in dermal thickness and improvement in joint mobility while internal organ involvement remained stable. They describe a shift in T-cell populations with an increase in Tr1 and Treg cells as early as after the second round of treatment with ECP, with a concomitant decrease in Th17 cells. Additionally, they describe a shift from pro- to anti-inflammatory and anti-fibrotic cytokines with an increase in IL-10, IL-1Ra, HGF and a decrease in TGF-beta
98 and CCL2, respectively. They observed a direct positive correlation in the reduction of a pro-inflammatory cell population, Th17, and skin thickness. The role of ECP has also been evaluated in other autoimmune disease states including pemphigus vulgaris [16], systemic lupus erythematosus [17] and rheumatoid arthritis [18]. While promising, the results in these diseases are based on smaller scale studies. Treatment with ECP has become quite relevant to other “autoreactive” disorders that may also benefit from an enhanced Treg cell response including GVHD and solid organ transplantation rejection. Conversely, in the case of CTCL, it might seem paradoxical that a treatment which produces Tregs could be useful for a malignancy, particularly when patients with the most intact host immune response and lowest circulating tumor burden appear to have the highest response rates. It has been postulated by some that Tregs may actually inhibit the proliferation of malignant CD4+ Tcells. Studies have shown that patients with early stage disease have an increased number of FoxP3+ T-cells in the skin in comparison to those with advanced tumor stage or large cell transformation [19,20]. Treatment with ECP may actually increase and strengthen the Treg population contributing to its ultimate success [21]. With regard to the transplantation setting, Perez and colleagues, first described the ability of ECP to tolerize an animal to a skin allograft. They were able to demonstrate an attenuated response to alloantigens both in vivo and in vitro in mice whose splenocytes were photoinactivated by UVA and 8-MOP [22]. A subsequent controlled trial by Barr et al., demonstrated a significant decrease in acute cardiac rejection and in CMV infection among patients who had ECP added to a standard triple immunosuppressive regimen as compared to patients not receiving ECP [23]. A proposed mechanism is through the generation of tolerogenic dendritic cells and an increase in number of regulatory T-cells with a suppressive phenotype [24]. Similarly, ECP is used in the setting of grade I and II acute GVHD [25,26] as well as chronic GVHD [27]. It is thought that the induction of Tregs allows for suppression of the vigorous donor response [21]. Finally, in murine models of contact hypersensitivity, ECP through the generation of IL-10 and induction of regulatory T-cells acts to inhibit the effector phase and sensitization of contact hypersensitivity [10].
How can we enhance the immunomodulatory effects of ECP? As our understanding of the immunomodulatory effects of ECP continues to expand, we have become more adept in adding supplementary therapeutic agents to enhance those effects. A key example is in the management of patients with CTCL. Rook et al., in as early as 1991, reported the beneficial effect of adding low dose interferon (IFN) alpha to ECP for patients with advanced CTCL [28]. Subsequent studies have confirmed that a multimodality approach to the management of CTCL patients, including immune augmentatory cytokines such as IFN-alpha and IFN-gamma, are associated with improved outcomes [29,30]. Similarly, the addition of immune modifying agents to ECP may provide significant benefit in managing patients with systemic sclerosis and other inflammatory conditions.
Editorial Sirolimus (Rapamycin), an mTOR inhibiter, can inhibit the differentiation of naïve T-cells to Th17 cells [31] and promote the generation and survival of Treg cells [32,33]. In addition, sirolimus has enhanced anti-fibrotic effects in mouse models of systemic sclerosis as well as other fibrotic disease states [34,35]. Vorinostat (Zolinza) is a histone deacetylase (HDAC) inhibitor approved for use in CTCL. Evidence has demonstrated further benefit of HDAC inhibitors through their ability to enhance the production and suppressive function of Foxp3+ Treg cells [36]. The combination of sirolimus and an HDAC inhibitor may lead to complete tolerance to an allograft in animal models. Bortezomib (Velcade) is a proteasome inhibitor used to treat multiple myeloma. Recent evidence has demonstrated that through inhibition of TGF-beta1 gene expression, Bortezomib can prevent both lung and skin fibrosis induced by bleomycin in mice [37]. Capitalizing on the anti-fibrotic effects of these medications in conjunction with ECP may prove beneficial in managing patients with systemic sclerosis and sclerodermatous chronic GVHD. Many of the immunosuppressive agents used today act by nonspecific global immunosuppression rendering a host at increased risk for opportunistic infections, development of malignant tumors, as well as other adverse effects. Aside from reports of transient hypotension and rarely, low-grade fevers and problems related to poor vascular access, ECP tends to be particularly well tolerated [25]. Most importantly, it does not place patients at increased risk for opportunistic infections and it allows for a dose reduction of a patient's immunosuppressive regimen. However, contraindications include severe cardiac or renal impairment, hypersensitivity to psoralen and certain coagulation disorders. In the future, the use of photopheresis might be superseded or complemented by methods aimed at directly infusing expanded populations of Tregs. Brunstein et al. established a method by which CD4+ CD25+ FoxP3+ T regulatory cells can be enriched from umbilical cord blood and injected back to the patient [38]. They demonstrated a reduction in the incidence of grade II-IV acute GVHD without significant associated comorbidity. This would provide a novel mechanism to boost the host's systemic immunoregulatory response. The article by Papp et al. does an excellent job in defining the immunologic profile of patients with systemic sclerosis undergoing treatment with ECP and its potential benefits. Future goals should be directed at the precise elucidation of the full mechanisms of action of ECP so that this treatment can be optimally harnessed for the full spectrum of responsive conditions.
References [1] A.H. Rook, B. Freundlich, B.V. Jegasothy, M.I. Perez, W.G. Barr, S.A. Jimenez, R.L. Rietschel, B. Wintroub, M.B. Kahaleh, J. Varga, et al., Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial, Arch. Dermatol. 128 (1992) 337–346. [2] R.M. Knobler, L.E. French, Y. Kim, E. Bisaccia, W. Graninger, H. Nahavandi, F.J. Strobl, E. Keystone, M. Mehlmauer, A.H. Rook, I. Braverman, A randomized, double-blind, placebo-
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Sara Samimi, M.D. Alain H. Rook, M.D.⁎ Department of Dermatology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA ⁎ Corresponding author at: One Convention Avenue, Department of Dermatology, 14 Penn Tower, Philadelphia, PA, USA. Fax:+1 215 615 4966. E-mail address: [email protected] (A.H. Rook).