[Frontiers in Bioscience 14, 4769-4777, January 1, 2009]
Extracorporeal photoimmunotherapy-photopheresis
1,2
Theresa Dani1, Robert Knobler2
TABLE OF CONTENTS
1. ABSTRACT
Extracorporeal photoimmunotherapy-photopheresis (ECP) is an immunomodulatory therapy, which basically consists of separating the patient's leucocyte rich plasma from the red blood cell fraction, followed by extracorporeal administration of a photosensitizer and UVA light prior to reinfusion of the treated cells. Successful use of ECP has been reported in patients with cutaneous T cell lymphoma, the Sezary syndrome variant, graft-versus-host disease, cardiac transplant rejection and other T cell mediated/autoimmune and autoimmune diseases. Apoptosis of malignant lymphocytes and presentation of their antigens to anti-tumor CD8+ T cells with induction of an anticlonotypic response by CD8+ effector cells against the CD4+ neoplastic T cells was one of the intial mechanisms of action proposed. The exact mechanism by which ECP exerts its therapeutic effect remains to be further explored and is still uncertain. The better understanding of its mode of action and the clinical benefits of ECP are important findings that provide additional tools to increase the therapeutic armamentarium in a number of acute and chronic T cell mediated diseases.
2. INTRODUCTION
Extracorporeal photochemotherapy or photopheresis (ECP) was first introduced in 1987 for the management of patients with cutaneous T cell lymphomas (CTCL) (1). Since then, the ECP has been applied as a main therapy for various other T cell mediated diseases in and beyond dermatology, including autoimmune diseases, rejection of solid-organ grafts and inflammatory dermatologic diseases (2-7). Up to the present it remains the only FDA approved tumor targeting selective immunotherapy for the treatment of cancer. Though many studies have been conducted, including animal models and in vitro studies, the exact mode of action on a molecular basis still remains unclear. The photopheresis procedure takes place in three steps: leukapheresis, photoactivation, and reinfusion (8-10). During photopheresis, the patients' plasma and leukocyte-rich fractions are separated by centrifugation, then passed through a thin, UV-penetrable plastic plate, followed by exposure to a photosensitizer. At present photosensitization is achieved by either giving 8-methoxypsoralen (8-MOP) to the patient 2 hours prior to the procedure, or by adding a photosensitizing agent directly into the leukocyte-rich fraction (e.g.: UVADEX). The latter avoids unwanted side effects such as nausea and provides a more consistent drug level within the machine (11). The treated leukocytes are re-infused after a minimum exposure of 1,5 hours. Depending on the underlying disease and various protocols, this treatment is usually repeated on 2 successive days, at 4 week intervals. The total UVA dose delivered has been determined to be 2 J/cm2. ECP is not inexpensive, somewhat time consuming and approved indications are restricted; side effects are minimal as the experience with this therapy spans over 20 years. In some patients, volume changes due to loading with physiological saline can lead to changes in blood pressure and congestive heart failure when predisposed. Anticoagulation can lead to bleeding complications and some patients complain about prolonged recumbency. Excessive frequency of treatment in some patients has been associated with a decrease in the red blood cell fraction requiring treatment. The photopheresis procedure is available worldwide today in over 150 centers.
3. HISTORY
Over 2 decades ago, Edelson and coworkers published the first encouraging results of the use of ECP in 37 patients with advanced cutaneous T cell lymphomas (CTCL) (1). The clinical thought derived from the observation that in an animal model, after lethally damaging an autoreactive T cell clone and subsequent re-infusion of viable autoreactive T cells, disease was not induced (12, 13). The basic hypothesis was that an induced clone-specific immune reaction might limit the activity of an aberrant population of T cells and could be of therapeutic value in patients with diseases mediated by circulating T cells (1, 8). Also the fact that psoralen-UVA treatment of the skin (PUVA) in these patients contributed to a systemic improvement supported this hypothesis.
The Sezary syndrome, a leukemic form of CTCL with erythroderma with often high numbers of circulating T cells in peripheral blood and an expected 5-year survival rate of 24% (14), supplied the perfect clinical setting. Twenty seven patients (73%) achieved response to treatment and in eleven successfully treated patients with CTCL of known clonal origin, several patterns of persistent T lymphocyte subset alterations were noted. T4 cells decreased and T8 cells increased, leading to a significant decrease in the T4/T8 ratio (8). The accessibility of subsets of leucocytes by ECP offered the perfect setting by which the lymphocytes could be damaged but at the same time retain their antigenicity until they were sequestered by an uninhibited immunologic response. Various studies followed, in vitro and in vivo studies, either to highlight the mechanism of action or to extend the therapeutic applicability of ECP for a variety of T cell mediated disorders including graft-versus-host disease (GVHD) (2, 15), scleroderma (8), solid organ transplant rejection (16, 17, 18), oral lichen planus (5), autoimmune bullous disorders (19).
4. MECHANISMS OF ACTION
4.1. General aspects
Photopheresis and its mechanism of action have been intensively studied in patients with Sezary syndrome (20). In this cohort of patients, the induction of an immune response against defined lymphocyte populations seems to account for the therapeutic effect. In these patients, complete clinical response has been shown to correlate with the complete disappearance of the malignant T cell clone (20). Even though the precise mechanism underlying the observed efficacy of ECP as a therapy still remains to be elucidated, some hypothetic mechanisms of action have been proposed with regard to the pathogenetic differences of the underlying T cell mediated diseases being treated. An important role is attributed to regulatory T cells (Tregs), which are naturally occurring CD4+CD25+ T cells, and whose main physiological role is to switch off autoreactive T cells, thus maintaining self-tolerance (21). Preliminary data shows that the percentage of circulating, functional Tregs can be increased after ECP (22), even though this increase does not easily translate into clinical improvement of patients with chronic graft versus host disease. Other experimental results implied that ECP can also lead to the maturation of dendritic cells from monocytes, the most efficient antigen presenting cells for induction off anti-tumor immunity (23). The development of clinically relevant anti-tumor response in numerous CTCL patients treated with ECP suggests that these responses are due, at least in part, to the generation of dendritic cells capable of ingesting apoptotic CTCL cells and presentation of their antigens to anti-tumor CD8+ T cells (23). Several studies have tried to identify the exact cells and their contents responsible for the action of ECP, one of them being the induction of lymphocyte apoptosis (2, 24). Following ECP induced apoptosis, normal T lymphocytes are replaced at a greater rate than malignant cells and migrate to the peripheral blood (24). Monocytes that do not become apoptotic, produce increased levels of TNFα, which can augment a number of antitumor immune responses (24). One important finding of numerous studies trying to highlight the immunogenic mechanism effected by ECP, is that it does not appear to suppress specific B cell function nor T cell responses, and therefore not induce a generalized immunosuppression (44). Observations in experimental animal models support the evidence that ECP induces specific immunity against pathogenic T cell clones, without suppressing the cellular nor humoral component of the immune system, thus not increasing, but actually reducing, the incidence of infections or neoplasms (44).
4.2. Specific aspects
4.2.1. Cutaneous T cell lymphomas
After the first therapeutic success in patients with refractory CTCL (1, 8), ECP has been studied in numerous therapeutic trials to assess the optimal indication and increase the therapeutic armamentarium for different stages of CTCL (26, 27, 28). In the management of CTCL, ECP is mainly used for the treatment of erythrodermic patients, including those with Sezary syndrome with a high number of circulating atypical mononuclear cells (Sezary cells). Overall response rates are reported between 31% and 86%, whereas rates for complete remission are much lower, ranging from 0 to 33% (29, 30, 31, 32). Individual clinical, immunological and laboratory entry data of patients and different pre-therapies may relate to the differences in response rates published. Favorable response rates to ECP have been associated with early intervention, normal to high CD8+ cell counts, discrete number of Sezary cells and sufficient immunologic reserve (33, 34, 26). However, some of these results are inconsistent, similar to studies reporting on survival data of patients with CTCL treated with ECP (35, 36). Median survival is dependent on the extent of disease, the presence of lymphadenopathy and hematologic involvement and is reported to range between 2,5 and 5 years (37,26). In studies with combination therapies, much longer median survival has been indicated (29, 38). Combination therapies used with ECP have become common and among the most often used are interferon-a (IFN-a ), total skin electron beam (TSEB), but also methotrexate and bexarotene (39). Several studies of ECP plus IFN-a have been published (38, 40, 41), but evidence is limited as none of these were prospective, randomized controlled trials, included patients with different disease stages and some had more than 2 other combination therapies used (38, 41). In erythrodermic patients with CTCL, fair evidence supports the combination of ECP and TSEB, as data showed a 3-year disease free survival of 81% (32, 42). While most observations support the use of ECP in stages III and IV of CTCL, studies have also been conducted in patients with early stage disease, such as stages IA-IIA, either as mono-therapy or in combination with retinoids, IFN-alpha and other systemic immunostimulatory agents (43). Interestingly, ECP mono- and combination-therapy in patients with early stages of disease disclosed similar response rates, but varied between 33-88% (43, 44). Despite often encouraging data, the long term course of disease and overall survival of patients with early stage CTCL does not appear at present to support the use of ECP in early stages of disease, but should be explored. Only large prospective randomized trials can answer these questions in a satisfactory manner. Predominant theories today explain the therapeutic benefit of photopheresis in CTCL by apoptotic malignant T cells that are phagocytosed by stimulated monocytes (14, 20, 24, 26). Then they are processed and presented by antigen presenting cells which evokes an anticlonotypic response by CD8+ effector cells against the CD4+ neoplastic T cells. On this basis, the reflow of phototreated cells to the patient appears central to ECP's mode of action.
4.2.2. GVHD
Graft-versus-host disease, complicating allogeneic bone marrow transplantation, has been successfully used in the treatment of acute and chronic GVHD for the past 13 years (45, 46, 47). Despite conventional and new therapies for the prevention or treatment of chronic GVHD, this syndrome continues to account for significant morbidity and mortality of affected patients (48). The pathogenesis of chronic GVHD is complex and involves an immune-mediated attack by transplanted donor lymphocytes and auto-reactive phenomena due to activation of immunologic pathways that bear similarities to those involved in several autoimmune disorders (49). Therefore, numerous reports have focused on the use of ECP in chronic steroid/immunosuppressive-refractory GVHD and demonstrated considerable efficacy, especially in patients with cutaneous and mucosal involvement. Response rates are high and vary in reports between 60 and 80% (46, 50, 51). The mechanism by which photopheresis is of therapeutic benefit in chronic GVHD is still unclear. In contrast to other established treatments for GVHD, it seems likely that a change in the regulation of cell function (dendritic cells/T cells), without removal of T cells or other cell fractions including antigen presenting cells, occurs in GVHD. In patients with detectable expanded clonal T cell populations in their peripheral blood, response to ECP treatment is 100% (52), suggesting the induction of an immune response against defined lymphocyte populations by ECP. Cells treated with photopheresis might induce an antigen-specific immune response directed to the pathogenic T cell populations without affecting general immunocompetence. In acute GVHD, a threatened complication with a survival rate of less than 30% (3), ECP has been introduced in patients with a steroid/immunosuppressive-refractory course. Results of these studies are inconsistent, but point to at a very promising adjunct therapy in patients with specific cutaneous and liver involvement (3, 32, 50). Improved survival in these patients could thus easily justify the high costs associated with ECP.
4.2.3. Scleroderma
Systemic sclerosis (scleroderma) is an autoimmune disorder, characterized by abnormal deposits of collagen in the skin and within visceral organs. Prognosis depends on the extent of disease and rates of progression. Therapeutic management in scleroderma is problematic, as prevalence is low and response rates vary according to individual progression of disease. Scleroderma has been linked to chronic graft-versus-host disease due to clinical and biologic similarities, and similar to patients with CTCL and improved response to ECP with higher amounts of clonal T cells in the peripheral blood, likewise results have been reported in patients with systemic sclerosis (53). Responsiveness to ECP in patients showing presence of expanded clonal T-cell populations is higher, though response to ECP does not seem to correlate with the disappearance of the clonally amplified T-cell populations (53). Many reports in the literature show either a beneficial effect of ECP on systemic sclerosis, or no significant benefit/worsening of scleroderma following ECP (54, 55, 56, 57, 58). Specifically improvement of the cutaneous component may override systemic response. Clonality of T cells in peripheral blood has been detected in different nonmalignant conditions (Hingorani), and evidence has been linked to clonal expansion and activation of auto-reactive T cells in certain autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis (60). In the named diseases, again T cells are central to the development of tissue damage and several hypotheses support an antigen-driven clonal expansion of these cells (57, 59). The mechanism of ECP in the successful treatment of scleroderma patients, again is unclear, but points at an abnormal immune activation by means of activated T cells within the peripheral blood and the sites of abnormal collagen production (61). Present experience for this indication suggests that ECP not alone but in combination with other drugs such as cyclophosphamide may improve the observed results.
4.2.4. Solid organ transplant rejection
4.2.4.1. Lung and heart
Allograft survival depends on the control of rejection response against donor molecules of the major histocompatibility complex (MHC). The suppression of the rejection cascade is of major importance for patients receiving an organ transplant. Apart from immunosuppressives and systemic corticosteroids, ECP has been used to reverse allograft rejection (62, 63, 64). The antigens are processed by antigen-presenting cells and presented in the context of their MHC molecules to effector T lymphocytes of the recipient. T cell receptor recognition of the antigenic peptides leads to a stable activation of T cell cytokine gene transcription, which ultimately stimulates the rejection cascade. Different studies have shown that the procedure of photopheresis inhibits the reactivity of the immunological apparatus against transplanted antigens in a specific manner (65). A parallel hypo-proliferative response against graft antigens, due to the generation of specific inhibitor cells and a specific suppression of cytotoxic T cells response versus donor antigens has also been shown (65, 66). The experimental data obtained in the study, support the hypothesis that photopheresis induces an anti-idiotypic response (65), and therefore seems to induce an inhibition of both humoral and cellular rejection after transplantation. Benefit of ECP for lung transplant rejection has been reported, though patient numbers are small (67). In acute lung rejection and in patients developing bronchiolitis obliterans syndrome, stabilization of the airflow obstruction and inhibition of rejection could be obtained without complications (68, 69, 70). A recent report has suggested that ECP might also modulate the number of peripheral T regulatory cells (CD4+ CD25+ T regs), as T reg cell kinetics showed stabilization or a slight increase, in lung transplant patients with clinical improvement following ECP (16).
In cardiac transplantation, photopheresis has gained broad clinical acceptance as an effective therapy for recurrent or persistent rejection (71). Achieved evidence supports the use of ECP in patients with acute cardiac rejection, as the alternative to increasing systemic corticosteroid pulses (72) and in recurrent acute cardiac rejection (73), which is defined as equal or greater than three consecutive episodes of acute rejection. Based on further studies, therapeutic indications have been extended to chronic cardiac rejection and to the prophylaxis of cardiac rejection (64, 71). The impact of photopheresis has been confirmed in a larger study with 36 patients at higher risk for cardiac rejection, who received ECP treatment. The study showed that ECP could reduce the risk of subsequent hemodynamic compromised rejection and /or death from rejection (17).
4.2.4.2. Kidney
ECP has also been reported to be helpful in the management of patients after kidney transplantation, though patient numbers have been small (18, 74). Most results indicate improvement in graft function after ECP in chronic renal allograft rejection as well as in single cases with acute rejection (75, 76), but evidence is poor.
Recently, photopheresis has been reported to be associated with improvement in a disease entity recently described as nephrogenic fibrosing dermopathy (NFD) or so called nephrogenic systemic fibrosis (NSF). This is a rare fibrosing skin disease of unknown etiology occurring in patients with terminal renal disease. The histology of NFD shows an increased number of dendritic cells, fibroblasts and thickened collagen fibers resembling scleromyxedema (77); recent data suggest a close association with the use of Gadolinium (79, 83) in this patient group. Apart from restoration of renal function by renal transplantation or recovery from acute renal failure whenever possible, extracorporeal photopheresis has shown to be of good clinical value even though numbers of patients reported on is small (78, 79).
4.2.5. Other diseases
ECP has been reported to be of benefit in some patients with chronic inflammatory skin diseases, such as lupus erythematodes (80), atopic eczema (81) and lichen ruber planus (82). In patients with erosive, therapy-refractory oral lichen ruber planus (LRP), therapeutic options are reduced after first line treatment with corticosteroids. The interest of ECP for severe recalcitrant forms of lichen planus has been raised in view of clinical benefits observed in patients with chronic lichenoid GVHD. Promising albeit preliminary results have shown that ECP shows efficacy in this group of patients (82), and a recent study with 12 patients reported a complete remission of 75% and a partial remission of 25% in patients with refractory LRP (5). Though these reports suggest a possible therapeutic role, at least as a second line option, in the treatment of oral LRP it has to be noted nevertheless, that ECP is expensive and time consuming and patients are immobilized for half a day for each session. However, as oral LRP is a localized disease with high recurrence rates, ECP needs to be confirmed as a useful treatment additive in larger studies, to determine its long-term safety and efficacy.
Another benefit of ECP has been acquainted in patients with blistering diseases, such as epidermolysis bullosa acquisita (84), pemphigus vulgaris and bullous pemphigoid (85, 86, 87). This special group of autoimmune bullous diseases in the skin, has been treated by ECP with substantial benefit (84, 85, 86). Published data on general therapeutic strategies in autoimmune blistering diseases is poor, partly reflecting the rarity of the disease as well as individual courses of disease and pre-therapies in these patients. Use of systemic corticosteroids is among the best established therapies, but the well-known spectrum of side effects and severe relapses following steroid withdrawal, limit their long-term use. ECP has led to partial or complete response in patients with recalcitrant pemphigus vulgaris (86) and also in patients with acquired epidermolysis bullosa (87) without noteworthy side effects. In patients with recalcitrant disease and failure of conventional treatment, ECP offers a well-balanced risk-benefit ratio and makes it a recommendable treatment option for drug-resistant bullous autoimmune diseases.
5. FUTURE PROSPECTS
The fact that ECP has clearly shown, in the clinical setting, the capacity to stimulate apparently opposed immune effects- the up-regulation of an anti-tumor response and the down-regulation of autoimmune diseases or allogeneic immune responses- will contribute to the amplification of therapeutic applications. An exciting important therapeutic improvement could be achieved in children with type I diabetes mellitus. Photopheresis showed an effect in addition to its powerful placebo effect, weak but significant on the disease process at the onset of type 1 diabetes, which was still noted after three years of follow up (88). Preliminary data also supports its use in a selected group of patients with Ulcerative colitis or Chron's disease (89). Future prospects point at more and extended applications of ECP in the therapeutic armamentarium of many other T cell mediated diseases. Randomized controlled studies with statistically significant results are needed to confirm the efficacy of these diseases. Though most studies tried to explain and highlight the exact mode of action, we have to admit that the exact course of immunologic action in patients undergoing ECP still remains uncertain at many levels. In summary, the major advances of photopheresis over conventional therapies for CTCL, GVHD and autoimmune diseases, its selectivity for the pathogenic clones via a non-toxic, steroid sparing therapeutic alternative makes ECP a unique, attractive and promising therapy.
6. REFERENCES
1. R. Edelson, C. Berger, F. Gasparro, B. Jegasothy, P. Heald, B. Wintroub, E. Vonderheid, R. Knobler, K. Wolff, G. Plewig et al.: Treatment of Cutaneous T- Cell Lymphoma by Extracorporeal Photochemotherapy: Preliminary Results. N Engl J Med 316 (6), 297 - 303 (1987) No DOI Found
2. J. Bladon, P.C. Taylor: Extracorporeal photopheresis induces apoptosis in the lymphocytes of cutaneous T-cell lymphoma and graft-versus-host disease. Br J haematology 107, 707-11 (1999)
doi:10.1046/j.1365-2141.1999.01773.x
PMid:10606873
3. H. Greinix, B. Volc - Platzer, P. Kahls, G. Fischer, A. Rosenmayr, F. Keil, H. Hönigsmann, and R. M. Knobler: Extracorporeal photchemopherapy in the treatment of severe steroid - refractory acute graft - versus - host disease: a pilot study. Blood 96, 2426 - 2431 (2000) No DOI Found
4. R. Dall' Amico, L. Murer: Extracorporeal photochemopherapy: a new therapeutic approach for allograft rejection. Transfusion and Apheresis Science 26, 197 - 204 (2002)
doi:10.1016/S1473-0502(02)00013-7
PMid:12126206
5. A. D. Guyot, D. Farhi, S. Ingen-Housz-Oro, A. Bussel, N. Parquet, C. Rabian, H. Bachelez, C. Frances: Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases. Br J Dermatol 156, 553-6 (2007)
doi:10.1111/j.1365-2133.2006.07647.x
PMid:17300247
6. R. Knobler, L. E. French, Y. Kim, E. Bisaccia, W. Graninger, H. Nahavandi, F.J. Strobl et al.: A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol 54, 793-99 (2006)
doi:10.1016/j.jaad.2005.11.1091
PMid:16635659
7. A. Thierry, G. Gorgun, K. B. Miller, T. F. Roberts, K. Sprague, D. P. Schenkein, F. M. Foss: Immunomodulatory effects of extracorporeal photochemopherapy in patients with extensive graft - versus - host disease. Blood 98, 1622 - 1625 (2001)
doi:10.1182/blood.V98.5.1622
PMid:11520818
8. R. L. Edelson, Photopheresis: a new therapeutic concept. Yale J Biol Med 62, 565-77 (1989) No DOI Found
9. I. Christensen, P. W. Heald: Photopheresis in the 1990's. J Clin Apheresis 6, 216-20 (1991)
doi:10.1002/jca.2920060409
PMid:1840064
10. A. Oliven, Y. Shechter: Extracorporeal photopheresis: a review. Blood Rev 15, 103-8 (2001)
doi:10.1054/blre.2001.0155
PMid:11409910
11. R. Knobler, F. Trautinger, W. Graninger et al.: Parenteral administration of 8-methoxypsoralen in photopheresis. J Am Acad Dermatol 28, 580-84 (1993) No DOI Found
12. A. Ben-Nun, H. Wekerle, I. R. Cohen: Vaccination against autoimmune encephalomyelitis with T lymphocyte line cells reactive against myelin basic protein. Nature 292, 60-1 (1981)
doi:10.1038/292060a0
PMid:6974307
13. J. Holoshitz, Y. Naparstek, A. Ben-Nun, I. R. Cohen: Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 219, 56-8 (1983)
doi:10.1126/science.6336851
PMid:6336851
14. E. C.Vonderheid, M.G. Bernengo, G. Burg et al.: Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 46, 95-106 (2002)
doi:10.1067/mjd.2002.118538
PMid:11756953
15. E. D. Seaton, R.M. Szydlo, E. Kanfer, J.F. Apperley, R. Russel - Lones: Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft - versus - host disease and analysis of predictors of response. Blood 102, 1217-1223 (2003)
doi:10.1182/blood-2002-11-3351
PMid:12714516
16. F. Meloni, A. Cascina, S. Miserere, C. Perotti, P. Vitulo, A. M. Fietta : Peripheral CD4 (+)CD25 (+) TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplant Proc 39, 213-7 (2007)
doi:10.1016/j.transproceed.2006.10.227
PMid:17275508
17. J. K. Kirklin, R. N. Brown, S. T. Huang, D. C. Naftel, S. M. Hubbard, B. K. Rayburn, D. C. McGiffin, R. B. Bourge, R. L. Benza, J. A. Tallaj, L. J. Pinderski, S. V. Pamboukian, J. F. George, M. Marques: Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant 25, 283-8 (2006)
doi:10.1016/j.healun.2005.10.004
PMid:16507420
18. J. H. Horina, R. R. Müllegger, S. Horn, H. Holzer, G. Halswachs, H. Kerl, P. Wolf: Photopheresis for renal allograft rejection. Lancet 346, 61 (1995)
doi:10.1016/S0140-6736(95)92696-8
19. U. Wollina, D. Lange, A. Looks: Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases. Dermatology 198, 140-4 (1999)
doi:10.1159/000018090
PMid:10325460
20. A. H. Rook, K. R. Suchin D. M. Kao, E. K. Yoo, W. H. Macey B. J. De Nardo et al: Photopheresis: clinical applications and mechanism of action. J Invest Dermatol Symp Proc 4, 85-90 (1999)
doi:10.1038/sj.jidsp.5640188
21. Z. Fehervari, S. Sakaguchi: Development and function of CD 25+CD4+ regulatory T cells. Current Opinion in Immunology 16, 203-208 (2004)
doi:10.1016/j.coi.2004.01.004
PMid:15023414
22. E. Biagi, I. Di Biaso, V. Leoni, G. Gaipa, V. Rossi, C. Bugarin, G. Renoldi, M. Parma, A. Balduzzi, P. Perseghin, and 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 (1), 31 - 39 (2007)
doi:10.1097/01.tp.0000267785.52567.9c
PMid:17627234
23. C. L. Berger, A.L. Xu, D. Hanlon, C. Lee, J. Schechner, E. Glusac, I. Christensen, E. Snyder, V. Holloway, R. Tigelaar, R.L. Edelson: Induction of Human Tumor - loaded Dendritic Cells. Int. J. Cancer 91, 438-447 (2001)
doi:10.1002/1097-0215(200002)9999:9999<::AID-IJC1073>3.0.CO;2-R
24. Yoo E.K., A.H. Rook, R. Elenitsas, F.P. Gasparro, B.R. Vowels: Apoptosis induction by ultraviolet light A and photochemotherapy in cutaneous T cell lymphoma: relevance to mechanism of therapeutic action. J Invest Dermatol 107, 235-242 (1996)
doi:10.1111/1523-1747.ep12329711
PMid:8757769
25. K. R. Suchin, M. Cassin, R. Washko, G. Nahass, M. Berkson, B. Stouch, B. R. Vowels, and A. H. Rook: Extracorporeal photochemotherapy does not suppress T - or B - cell responses to novel or recall antigens. J Am Acad Dermatol 41 (6) 980 - 986 (1999)
doi:10.1016/S0190-9622(99)70257-4
PMid:10570384
26. P. Heald, A. Rook, M. Perez et al.: Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol 27, 427-33 (1992) No DOI Found
27. J.A. Zic, G.P. Stricklin, J. P. Greer et al.: Long-term follow-up of patients with cutaneous T-cell lymphoma with treated with extracorporeal photochemotherapy. J Am Acad Dermatol 35, 935-45 (1996)
doi:10.1016/S0190-9622(96)90118-8
PMid:8959953
28. H. P. Gollnick, M. Owsianowski, J. Ramaker, S. C. Chun, C. E. Orfanos: Extracorporeal photochemotherapy- a new approach for the treatment of cutaneous T-cell lymphomas. Recent Results Cancer Res 139, 409-15 (1995) No DOI Found
29. J. A. Zic: The treatment of cutaneous T-cell lymphoma with photopheresis. Dermatol Ther 16, 337-346 (2003)
doi:10.1111/j.1396-0296.2003.01646.x
PMid:14686977
30. R. Russell-Jones: Extracorporeal photopheresis in cutaneous T-cell lymphoma: inconsistent data underline the need for randomized studies. Br J Dermatol 142, 16-21 (2000)
doi:10.1046/j.1365-2133.2000.03286.x
PMid:10651689
31. H. K. Koh, B. E. Davis, T. Meola et al.: Extracorporeal photopheresis for the treatment of 34 patients with cutaneous T-cell lymphoma (CTCL). J Invest Dermatol 102, 567 (1994) No DOI Found
32. 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 the British Photodermatology Group and the U.K. Skin Lymphoma Group. Br J Dermatol 154, 7-20 (2006)
doi:10.1111/j.1365-2133.2005.06857.x
PMid:16403088
33. R. Knobler, C. Jantschitsch: Extracorporeal photochemoimmunotherapy in cutaneous T-cell lymphoma. Transfusion and Apheresis Science 28, 81 - 89 (2003)
doi:10.1016/S1473-0502(02)00103-9
PMid:12620272
34. R. Knobler, M. Girardi: Extracorporeal photochemoimmunotherapy in cutaneous T cell lymphomas. Ann NY Acad Sci 941, 123-38 (2001) No DOI Found
35. A. V. Evans, B.P. Wood, J.J. Scarisbrick, E.A. Fraser- Andrews, S. Chinn, A. Dean, P. Watkins, S.J. Whittaker, R. Russel-Jones: Extracorporeal photopheresis in Sézary Syndrome: hematologic parameters as predictor of response. Blood 98, 1298-301 (2001)
doi:10.1182/blood.V98.5.1298
PMid:11520774
36. J. J. Scarisbrick, S.J. Whittaker, A.V. Evans, E.A. Fraser- Andrews, F.J. Child, A. Dean, R. Russel-Jones: Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Blood 97, 624-30 (2001)
doi:10.1182/blood.V97.3.624
PMid:11157477
37. Y. H. Kim, A. Varghese, R. T. Hoppe: Prognostic factors in erythrodermic mycosis fungoides and the Sezary syndrome. Arch Dermatol 131, 1003-8 (1995)
doi:10.1001/archderm.131.9.1003
PMid:7661601
38. S. L. Gottlieb, J. T. Wolfe, F. E. Fox et al.: Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10 year experience at a single institution. J Am Acad Dermatol 35, 946-57 (1996)
doi:10.1016/S0190-9622(96)90119-X
PMid:8959954
39. P. Tsirigotis, V. Pappa, S. Papageorgiu, V. Kapsimali, V. Giannopoulou, I. Kaitsa, K. Girkas, E. Papageorgiu, N. Stavrianeas, T. Economopoulos, J. Dervenoulas: Extracorporeal photopheresis in combination with bexarotene in the treatment of mycosis fungoides and Sézary syndrome. Br J Dermatol 156, 1362-1402 (2007)
doi:10.1111/j.1365-2133.2007.07901.x
PMid:17459033
40. U. Wollina, A. Looks, J. Meyer et al: Treatment of stage II cutaneous T cell lymphoma with interferon alfa 2a and extracorporeal photochemotherapy: a prospective controlled trial. J Am Acad Dermatol 44, 253-60 (2001)
doi:10.1067/mjd.2001.110645
PMid:11174383
41. E. Bisaccia, J. Gonzalez, M. Palangio et al.: Extracorporeal photochemotherapy alone or with adjuvant treatment of cutaneous T- cell lymphoma: a 9-year retrospective study in a single institution. J Am Acad Dermatol 43, 263-71 (2000)
doi:10.1067/mjd.2000.104852
PMid:10906649
42. L. D. Wilson, G. W. Jones, D. Kim et al.: Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J Am Acad Dermatol 43, 54-60 (2000)
doi:10.1067/mjd.2000.105510
PMid:10863224
43. J. D. Miller, E. D. Kirkland, D. Santo Domingo, H. Scull, B. Jekutis, M. Dallas, K. D. Cooper, E. D. Baron: Review of extracorporeal photopheresis in early-stage (IA,IB, and IIA) cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed 23, 163-171 (2007)
doi:10.1111/j.1600-0781.2007.00300.x
44. K. R. Suchin, A. J. Cucchiara, S. L. Gottlieb et al.: Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 138, 1054-1060 (2002)
doi:10.1001/archderm.138.8.1054
PMid:12164743
45. M. Oswianowski, H. Gollnick, W. Siegert et al.: Successful treatment of chronic graft-versus-host disease with extracorporeal photopheresis. Bone Marrow Transplant 14, 845-48 (1994) No DOI Found
46. H. T. Greinix, B. Volc-Platzer, W. Rabitsch et al.: Successful use of extracorporeal photochemotherapy in the treatment of severe and chronic graft-versus-host disease. Blood 92, 3098-104 (1998) No DOI Found
47. F. J. Child, R. Ratnavel, P. Watkins et al.: Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 23, 881-87 (1999)
doi:10.1038/sj.bmt.1701733
PMid:10338042
48. K. M. Sullivan, R. P. Witherspoon, R. Storb et al.: Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood 72, 555-561 (1998) No DOI Found
49. J. L. Ferrara, H. J. Deeg: Graft-versus-host disease. New Engl J Med 324, 667-674 (1991) No DOI Found
50. E. P. Smith, I.Sniecinsky, A. C. Dagis, P. M. Parker, D. S. Snyder, A. S. Stein, A. Nademanee, M. R. O'Donnell, A. Molina, G. M. Schmidt, D. E. Stepan, N. Kapoor, J. C. Niland, S. J. Forman: Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease. Biol Blood Marrow Transplant 4, 27-37 (1998) No DOI Found
51. E. Dippel, S. Goerdt, C. E. Orfanos: Long-term extracorporeal photoimmunotherapy for treatment of chronic cutaneous graft-versus-host disease: observations in four patients. Dermatology 198, 370-74 (1999)
doi:10.1159/000018150
PMid:10449936
52. L. E. French, T. Alcindor, M. Shapiro, K. S. McGinnis, D. J. Margolis, D. Porter, D. G. B. Leonard, A. H. Rook, F. Foss: Graft - versus - host disease. Identification of amplified clonal T cell populations in the blood of patients with chronic graft - versus - host disease: positive correlation with response to photopheresis. Bone marrow transplantation 30 (8), 509 - 515 (2002)
doi:10.1038/sj.bmt.1703705
PMid:12379890
53. L.E. French, S. R. Lessin, K. Addya, B. Denardo, D. J. Margolis, D. G. B. Leonard, A. H. Rook: Identification of Clonal T Cells in the bood of ptients with systemic sclerosis. Positive crrelation wth response to photopheresis. Arch Dermatol 137, 1309-1313 (2001) No DOI Found
54. R. Knobler, L. R. French, Y. Kim, E. Bisaccia, W. Graninger, H. Nahavandi, F. J. Strobl, E. Keystone, M. Mehlmauer, A. Rook, I. Braverman: A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol 54, 793-99 (2006)
doi:10.1016/j.jaad.2005.11.1091
PMid:16635659
55. K. Krasagakis, E. Dippel, J. Ramaker et al: Management of severe scleroderma with with long-term extracorporeal photopheresis. Dermatology 196, 309-15 (1998)
doi:10.1159/000017927
PMid:9621138
56. B. Cribier, T. Faradji, C. Le Coz et al.: Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology 191, 25-31 (1995) No DOI Found
57. D. N. H. Enomoto, J. R. Mekkes, P. M. M. Bossuyt et al.: Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis). J Am Acad Dermatol 41, 915-22 (1999)
doi:10.1016/S0190-9622(99)70246-X
PMid:10570373
58. A. H. Rook, B. Freundlich, B. V. Jegasothy et al.: Treatment of systemic sclerosis with extracorporeal photochemotherapy. Arch Dermatol 128, 337-46 (1992)
doi:10.1001/archderm.128.3.337
PMid:1550365
59. R. Hingorani, I. H. Choi, P. Akolkar et al.: Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol 151, 5762-5769 (1993) No DOI Found
60. C. Olive: T cell receptor usage in autoimmune disease. Immunol Cell Biol 73, 297-307 (1995)
doi:10.1038/icb.1995.46
PMid:7493765
61. M. I. Perez, R. I. Edelson, L. John, L. Laroche, C. L. Berger: Inhibition of anti-skin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET cells). Yale J Biol Med 62, 595-609 (1989) No DOI Found
62. R. Dall'Amico, L. Murer: Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection. Transfus Apher Sci 26, 197-204 (2002)
doi:10.1016/S1473-0502(02)00013-7
PMid:12126206
63. R. Dall'Amico, G. Montini, L. Murer, B. Andreetta, G. Zacchello, A. Gambino, G. Feltrin, A. Caforio, V. Tursi, U. Livi: Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection. Int J Artif Organs 23, 49-54 (2000) No DOI Found
64. M. Barr, B. Meiser, H. Eisen et al: Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 339, 1744-51 (1998)
doi:10.1056/NEJM199812103392404
PMid:9845709
65. M. I. Perez, R. I. Edelson, R. L. Laroche, et al.: Inhibition of anti-skin allograft immunity by infusion with syngeneic photoinactivated effector lymphocytes. J Invest Dermatol 92, 669-76 (1989)
doi:10.1111/1523-1747.ep12696853
PMid:2523941
66. R. L. Edelson, P. W. Heald, M. I. Perez, C. Berger: Extracorporeal photochemotherapy. Biol Ther Cancer Updates 4, 1-8 (1994) No DOI Found
67. B. S. Slovis, J. E. Loyd, L. E. King Jr.: Photopheresis for chronic rejection of lung allografts. N Engl J Med 332, 962, 1995
doi:10.1056/NEJM199504063321417
PMid:7877665
68. C. T. Salerno, S. J. Park, N. S. Kreykes et al.: Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 117, 1063-9 (1999)
doi:10.1016/S0022-5223(99)70241-2
PMid:10343253
69. J. Villanueva, S. M. Bhorade, J. A. Robinson et al.: Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 5, 44-47 (2000)
70. G. Andreu, A. Achkar, J. P. Couetil et al. Extracorporeal photochemotherapy treatment for acute lung rejection episode. J Heart Lung Transplant 14, 793-6 (1995) No DOI Found
71. M. L. Barr, C. J. Baker, F. A. Schenkel: Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac transplantation. Clin Transplant 14, 162-6 (2000)
doi:10.1034/j.1399-0012.2000.140211.x
PMid:10770423
72. M. E. Billingham, N. R. B. Cary, M. E. Hammond et al: A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. J Heart Tranplant 9, 587-93 (1990) No DOI Found
73. R. Dall'Amico, U. Livi, A. Milano et al.: Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation 60, 1-4 (1995) No DOI Found
74. R. Dall'Amico, L. Murer, G. Montini et al.: Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol 9, 121-7 (1998)
doi:10.1159/000017034
PMid:9621997
75. G. Sunder-Plassmann, W. Druml, R. Steininger et al.: Renal allograft rejection controlled by photopheresis. Lancet 346, 506 (1995)
doi:10.1016/S0140-6736(95)91355-6
76. J.T. Wolfe, J. E. Tomaszewski, R. A. Grossman et al.: Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation and review of the literature. J Clin Apheresis 11, 36-41 (1996)
doi:10.1002/(SICI)1098-1101(1996)11:1<36::AID-JCA8>3.0.CO;2-C
PMid:8722721
77. N. Scheinfeld: Nephrogenic fibrosing dermopathy: a comprehensive review for the dermatologist. Am J Clin Dermatol 7, 237-47 (2006)
doi:10.2165/00128071-200607040-00005
PMid:16901184
78. M. Gilliet, A. Cozzio, G. Burg, F. O. Nestle: Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 152, 531-6 (2005)
doi:10.1111/j.1365-2133.2005.06434.x
PMid:15787823
79. H. Richmond, J. Zwerner, Y. Kim, D. Florentino: Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol 143, 1025-30 (2007)
doi:10.1001/archderm.143.8.1025
PMid:17709661
80. H. I. Richter, J. Krutman, G. Goerz: Extracorporeal photopheresis in therapy-refractory disseminated discoid lupus erythematosus. Hautarzt 49, 487-91 (1998)
doi:10.1007/s001050050775
81. G. Mohla, N. Horvath, S. Stevens: Quality of life improvement in a patient with severe atopic dermatitis treated with photopheresis. J Am Acad Dermatol 40, 780-82 (1999)
doi:10.1016/S0190-9622(99)70167-2
PMid:10321614
82. P. A. Bécherel, A. Bussel, O. Chosidow et al: Extracorporeal photochemotherapy for chronic erosive lichen planus. Lancet 351, 805 (1998)
doi:10.1016/S0140-6736(05)78932-7
83. L. Carallini, C. Abaterusso, V. Bedogna, N. Petrica, C. Loschia and A. Lupo: Nephrogenic systemic fibrosis. G Ital Nefrol 25 (1), 14-20 (2008) No DOI Found
84. J. L. Miller, G. P. Stricklin, J. D. Fine et al: Remission of severe epidermolysis bullosa acquisita induced by extracorporeal photochemotherapy. Br J Dermatol 133, 467-71 (1995)
doi:10.1111/j.1365-2133.1995.tb02680.x
PMid:8547007
85. A. H. Rook, B. V. Jegasothy, P. W. Heald et al.: Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med 112, 303-5 (1990) No DOI Found
86. H. P. M. Gollnick, M. Owsianowski, K.M.Taube, C. E. Orfanos: Unresponsive severe generalised pemphigus vulgaris successfully controlled by extracorporeal photopheresis. J Am Acad Dermatol 28, 122-24 (1993) No DOI Found
87. D. T. Woodley, J. Remington, M. Chen: Autoimmunity to Type VII Collagen: Epidermolysis bullosa acquisita. Clin Rev Allergy Immunol 33, 78-84 (2007)
doi:10.1007/s12016-007-0027-6
88. J. Judvigsson, U. samuelsson, J. Ernerudh, C. Johansson, L. Steinhammar, G. Berlin: Photpheresis at onset of type 1 diabetes: a randomised, double blind, placebo controlled trial. Arch Dis Child 85, 149-54 (2001)
doi:10.1136/adc.85.2.149
PMid:11466190 PMCid:1718876
89. W. Reinisch, H. Nahavandi, R. Santella, Y. Zhang, C. Gasche, G. Moser, T. Waldhör, A. Gangl, H. Vogelsang, R. Knobler:Extracorporeal photochemotherapie in patients with steroid- dependent Crohn's disease: a prospective pilot study.Aliment Pharmacol Ther15 (9),1313- 22 (2001)
doi:10.1046/j.1365-2036.2001.01054.x
Abbreviations: CTCL: Cutaneous T - cell lymphoma, ECP: Extracorporeal photopheresis or extracorporeal photoimmunotherapy, FDA: Food and Drug Administration, the Consumer Protection Agency of the US Government which monitors medical devices, foods, drugs, biologics, veterinary medicine and more, GVHD: Graft - versus - host - disease, INF: Interferon, MHC: Major histocompatibility complex, MOP: Methoxy psoralen, NFD: Nephrogenic fibrosing dermatopathy , same as NSF, NSF: Nephrogenic systemic fibrosis, LRP: Lichen ruber planus, PUVA: a therapy combining the administration of the photosensitizer psoralen and UV-A irradiation, TSEB: Total skin electron beam , T regs: T regulatory cells
Key Words: Photopheresis, Photoimmunotherapy, Cutaneous T cell lymphoma, GVHD, Transplant rejection, Scleroderma, Review
Send correspondence to: Theresa Dani, Dept. of Dermatology, Medical University of Vienna, Währingergürtel 18 - 20, A-1090 Vienna, Austria, Tel: 0043-1-40400-7702, Fax: 0043-1-40812-87, E-mail:theresa.dani@meduniwien.ac.at