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Photopheresis in transplantation: future research and directions
Photopheresis
Photopheresis in Transplantation: Future Research and Directions M.L. Barr
T
HE DRAMATIC improvements seen in the field of transplantation in the past several decades have been in large part due to the evolution of immunosuppressive agents from those having effects on all bone-marrow– derived cellular components to the development of drugs and techniques aimed at T- and, to a lesser degree, Blymphocyte populations. Current clinical regimens with cyclosporine (CyA) or tacrolimus-based immunosuppression, azathioprine or mycophenolate mofetil, corticosteroids, with or without antibody induction protocols, have only partially reduced the incidence of acute cellular rejection. In addition, corticosteroid and/or antibody resistant rejection, while a less common problem, continues to be associated with a high incidence of graft failure and patient mortality. Of greater concern is that little progress has been made in regards to decreasing chronic forms of rejection (such as bronchiolitis obliterans, coronary vasculopathy) associated with late graft failure. Finally, the short- and long-term success in small bowel, lung, and bone marrow transplantation continues to be highly problematic with current protocols. These various manifestations of allograft-specific under-immunosuppression are complicated by concurrent problems with nonspecific pan-immunosuppression of the recipient, and there remains a significant risk of infections and malignancy as well as of side effects due to the direct toxicity of currently used immunosuppressive agents (ie, renal dysfunction, diabetes, osteoporosis, etc.). These clinical challenges combined with the inability to target individual clones of pathogenic effector T cells and a need to modify B-cell and antibody-mediated humoral responses has led to the investigation of the utility of photopheresis for modulating the immune response in a
less toxic and perhaps more selective manner. Photopheresis is a technique in which the patient’s peripheral blood mononuclear cells, in the presence of a photoactivatable compound, such as 8-methoxypsoralen, are exposed extracorporeally to ultraviolet A light. Blood is usually removed via a peripheral intravenous line. Utilizing a cell separator, the leukocyte-depleted blood is returned to the patient while the leukocyte-enriched plasma, containing either systemically absorbed or directly administered liquid 8-methoxypsoralen, is exposed to ultraviolet light in the 320 to 400 nm range. The photoexposed white cells are then returned to the patient. The entire procedure usually can be completed in a total of 4 hours. The photoactivated 8-methoxypsoralen covalently binds to DNA pyrimidine bases, cell surface molecules, and cytoplasmic components in the exposed white cells.1 The induction of 8-methoxypsoralenDNA crosslinks and photoadducts results in a lethal defect and the reinfused cells die gradually in the recipient over a 1- to 2-week interval. The reinfused altered lymphocytes produce an autologous suppressor response that targets unirradiated T cells of similar clones via an ill-defined mechanism. Photopheresis has been shown to be efficacious in a number of nontransplant disease states2 including cutaneous T-cell lymphoma, scleroderma, pemphigus vulgaris, systemic lupus erythematosus, and rheumatoid arthritis; all of these disease states are in part potentially mediated by
From the Division of Cardiothoracic Surgery, University of Southern California, Los Angeles, California, USA. Address reprint requests to Mark L. Barr, MD, Division of Cardiothoracic Surgery, 1510 San Pablo St, Los Angeles, CA 90033.
0041-1345/98/$19.00 PII S0041-1345(98)00608-3
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2248
Transplantation Proceedings, 30, 2248–2250 (1998)
PHOTOPHERESIS
expanded populations of unregulated effector T cells. Results of experimental work with 8-methoxypsoralen and ultraviolet A light treatment in murine3 and primate4 transplantation models led to clinical applications in solid organ transplantation. Research in the transplantation arena, in the past, has been single center clinical experiences5–10 involving the use of both oral and extracorporeal liquid 8-methoxypsoralen. Prior work9,11 has confirmed the highly unpredictable nature of oral 8-methoxypsoralen and the resulting blood level, and demonstrates that the extracorporeal addition of the liquid form results in reliable levels in the buffy coat. In view of these findings, all future work in photopheresis should probably be performed utilizing the liquid formulation with extracorporeal exposure. This also allows future studies involving exposure of the lymphocytes to varying quantifiable concentrations of 8-methoxypsoralen. The need for information generated from larger, multicenter studies should be addressed by trials that are underway in several areas of organ transplantation. An international, multicenter, FDA monitored, randomized study in cardiac transplant recipients assessing the safety and efficacy of maintenance photopheresis treatments added to a CyA-based triple drug regimen has recently been completed with final analysis pending. Liquid 8-methoxypsoralen (Uvadex) and the Therakos UVAR system (both from Therakos, Exton, Penn.) were employed in this study involving a total of 12 two-day-cycles of photopheresis during the first 6-month postoperative period. Maintenance immunosuppression and steroid taper, definition and treatment of rejection episodes, use of prophylactic antibiotics, and cardiac biopsy schedules have all been rigorously standardized among the participating centers with blinded core laboratory facilities utilized for analysis of cardiac biopsies and cytomegalovirus (CMV) DNA detection. Increasing anecdotal experience with photopheresis for resistant rejection in cardiac, pulmonary, renal, and bone marrow transplantations has led to the development of “rescue” protocols. The problematic treatment of refractory cardiac rejection is being evaluated in an ongoing FDA-monitored, open-label rescue study. Patients entered in this trial are those with an ongoing rejection unresponsive to intravenous steroids and/or polyclonal or monoclonal antibodies. All qualifying rejection episodes are International Society for Heart and Lung Transplantation (ISHLT) grade 3A or greater with lesser grades eligible for entry only if accompanied by hemodynamic compromise. Similarly, an open-label rescue study for lung transplant patients with refractory acute or chronic rejection is underway. The acute rejection must be biopsy proven to be ISHLT grade A2 or greater and chronic rejection must be proven by pathology and pulmonary function tests consistent with early bronchiolitis obliterans. Both of these rescue studies involve a photopheresis treatment frequency of 2 consecutive days per week for 4 weeks, and if clinical improvement is noted, continued treatment at 2-week and then monthly intervals is allowed. While there has been only limited anecdotal experience in the past with photo-
2249
pheresis in the prevention or treatment of graft-versus-host disease (GVHD) in bone marrow transplant recipients, an open-label rescue trial of patients with refractory chronic GVHD is currently underway. The patient must have failed to respond to corticosteroids and have GVHD with onset greater than 2 months after transplantation. At least one histologically diagnosed finding and one clinical feature must be present at the time of entry into the study. Histologic findings include a liver, skin, or mucosal biopsy consistent with chronic GVHD or histologically confirmed bronchiolitis obliterans. Clinical findings include skin thickening, sclerosis, hyper/hypopigmentation, or ulceration; joint contracture or fascial thickening; oral ulcerations; or unexplained diarrhea. Other clinical areas of interest for future studies include prophylactic photopheresis to prevent acute and/or chronic rejection in lung and small bowel transplantation in which current results with conventional immunosuppressants have been disappointing. Studies aimed at preventing and/or treating acute cellular and/or chronic vascular rejection; the effect on short- and long-term graft survival; the potential of the therapy to have beneficial antiviral (ie, anti-CMV) effects; and the effect on pretransplant sensitized patients (especially in renal transplantation) are potential areas to explore in all types of solid organ transplantation. Finally, potential improvements in the current design of the disposable photopheresis system circuit to allow a lower extracorporeal volume (which would allow future studies in the pediatric population), a shorter treatment time, and a decrease in the cost of treatments, would be highly desirable. Perhaps of greatest importance to the future of this immunomodulating technology is the characterization and isolation of the transplant recipient’s immune response to the treatment. There are various theories3,12–15 regarding the potential mechanisms involved including generation of CD8 positive clonotypic T cells, increased expression and/or recognition of immunogenic peptides in HLA clefts, inhibition of second signal transmission from antigen presenting cells, and production of cytokines by the extracorporeally treated leukocytes. Future experimental and clinical work will need to establish the optimal treatment frequency and duration required to maintain a beneficial immunologic effect. The subsequent determination of the minimal frequency and duration of required treatments will be particularly important from a cost-containment viewpoint. Potential synergy with other immunoregulatory techniques (such as plasmapheresis or intravenous immunoglobulin infusion) or immunoregulatory agents (such as alpha and gamma interferon, tumor necrosis factor, and IL-12), that have been used experimentally in the treatment of autoimmune diseases and cutaneous T-cell lymphoma,16 need to be investigated in transplantation. Studies involving the effect of photopheresis on tolerance induction and microchimerism will also be of interest. The current studies underway as well as future experimental and clinical work should help to define the long-term role of this novel, safe, and nontoxic
2250
immune modifying technology in the transplantation setting. REFERENCES 1. Gasparro F, Dall’Amico R, Goldminz D, et al: Yale J Biol Med 62:579, 1989 2. Rook A, Cohen J, Lessin S, et al: Derm Clin 11:339, 1993 3. Perez M, Edelson R, Laroche L, et al: J Invest Dermatol 92:669, 1989 4. Pepino P, Berger C, Fuzesi L, et al: Eur Surg Res 21:105, 1989 5. Rose E, Barr M, Xu H, et al: J Heart Lung Transplant 11:746, 1992 6. Costanzo-Nordin M, Hubbell E, O’Sullivan E, et al: Circulation 86:242, 1992 7. Rose E, Pepino P, Barr M, et al: J Heart Lung Transplant 11:S120, 1992
BARR 8. Barr M, McLaughlin S, Murphy M, et al: Transplant Proc 27:1993, 1995 9. Meiser B, Kur F, Reichenspurner H, et al: Transplantation 57:563, 1994 10. Dall’Amico R, Livi U, Milano A, et al: Transplantation 60:45, 1995 11. Knobler R, Trautinger F, Graninger W, et al: J Am Acad Dermatol 28:580, 1993 12. Lider O, Reshef T, Beraud E, et al: Science 239:181, 1988 13. Berger C, Perez M, Laroche L, et al: J Invest Dermatol 94:52, 1990 14. Heald P, Kim H, Perez M, et al: J Clin Apheresis 10:144, 1995 15. Edelson R, Perez M, Heald P, et al: In DeVita V, Hellman S, Rosenberg S (eds): Biologic Therapy of Cancer. Philadelphia: JB Lippincott; 1994, p 1 16. Wolfe J, Lessin S, Singh A, et al: Artific Organs 18:888, 1994
Photopheresis in Transplantation: Future Research and Directions M.L. Barr
T
HE DRAMATIC improvements seen in the field of transplantation in the past several decades have been in large part due to the evolution of immunosuppressive agents from those having effects on all bone-marrow– derived cellular components to the development of drugs and techniques aimed at T- and, to a lesser degree, Blymphocyte populations. Current clinical regimens with cyclosporine (CyA) or tacrolimus-based immunosuppression, azathioprine or mycophenolate mofetil, corticosteroids, with or without antibody induction protocols, have only partially reduced the incidence of acute cellular rejection. In addition, corticosteroid and/or antibody resistant rejection, while a less common problem, continues to be associated with a high incidence of graft failure and patient mortality. Of greater concern is that little progress has been made in regards to decreasing chronic forms of rejection (such as bronchiolitis obliterans, coronary vasculopathy) associated with late graft failure. Finally, the short- and long-term success in small bowel, lung, and bone marrow transplantation continues to be highly problematic with current protocols. These various manifestations of allograft-specific under-immunosuppression are complicated by concurrent problems with nonspecific pan-immunosuppression of the recipient, and there remains a significant risk of infections and malignancy as well as of side effects due to the direct toxicity of currently used immunosuppressive agents (ie, renal dysfunction, diabetes, osteoporosis, etc.). These clinical challenges combined with the inability to target individual clones of pathogenic effector T cells and a need to modify B-cell and antibody-mediated humoral responses has led to the investigation of the utility of photopheresis for modulating the immune response in a
less toxic and perhaps more selective manner. Photopheresis is a technique in which the patient’s peripheral blood mononuclear cells, in the presence of a photoactivatable compound, such as 8-methoxypsoralen, are exposed extracorporeally to ultraviolet A light. Blood is usually removed via a peripheral intravenous line. Utilizing a cell separator, the leukocyte-depleted blood is returned to the patient while the leukocyte-enriched plasma, containing either systemically absorbed or directly administered liquid 8-methoxypsoralen, is exposed to ultraviolet light in the 320 to 400 nm range. The photoexposed white cells are then returned to the patient. The entire procedure usually can be completed in a total of 4 hours. The photoactivated 8-methoxypsoralen covalently binds to DNA pyrimidine bases, cell surface molecules, and cytoplasmic components in the exposed white cells.1 The induction of 8-methoxypsoralenDNA crosslinks and photoadducts results in a lethal defect and the reinfused cells die gradually in the recipient over a 1- to 2-week interval. The reinfused altered lymphocytes produce an autologous suppressor response that targets unirradiated T cells of similar clones via an ill-defined mechanism. Photopheresis has been shown to be efficacious in a number of nontransplant disease states2 including cutaneous T-cell lymphoma, scleroderma, pemphigus vulgaris, systemic lupus erythematosus, and rheumatoid arthritis; all of these disease states are in part potentially mediated by
From the Division of Cardiothoracic Surgery, University of Southern California, Los Angeles, California, USA. Address reprint requests to Mark L. Barr, MD, Division of Cardiothoracic Surgery, 1510 San Pablo St, Los Angeles, CA 90033.
0041-1345/98/$19.00 PII S0041-1345(98)00608-3
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2248
Transplantation Proceedings, 30, 2248–2250 (1998)
PHOTOPHERESIS
expanded populations of unregulated effector T cells. Results of experimental work with 8-methoxypsoralen and ultraviolet A light treatment in murine3 and primate4 transplantation models led to clinical applications in solid organ transplantation. Research in the transplantation arena, in the past, has been single center clinical experiences5–10 involving the use of both oral and extracorporeal liquid 8-methoxypsoralen. Prior work9,11 has confirmed the highly unpredictable nature of oral 8-methoxypsoralen and the resulting blood level, and demonstrates that the extracorporeal addition of the liquid form results in reliable levels in the buffy coat. In view of these findings, all future work in photopheresis should probably be performed utilizing the liquid formulation with extracorporeal exposure. This also allows future studies involving exposure of the lymphocytes to varying quantifiable concentrations of 8-methoxypsoralen. The need for information generated from larger, multicenter studies should be addressed by trials that are underway in several areas of organ transplantation. An international, multicenter, FDA monitored, randomized study in cardiac transplant recipients assessing the safety and efficacy of maintenance photopheresis treatments added to a CyA-based triple drug regimen has recently been completed with final analysis pending. Liquid 8-methoxypsoralen (Uvadex) and the Therakos UVAR system (both from Therakos, Exton, Penn.) were employed in this study involving a total of 12 two-day-cycles of photopheresis during the first 6-month postoperative period. Maintenance immunosuppression and steroid taper, definition and treatment of rejection episodes, use of prophylactic antibiotics, and cardiac biopsy schedules have all been rigorously standardized among the participating centers with blinded core laboratory facilities utilized for analysis of cardiac biopsies and cytomegalovirus (CMV) DNA detection. Increasing anecdotal experience with photopheresis for resistant rejection in cardiac, pulmonary, renal, and bone marrow transplantations has led to the development of “rescue” protocols. The problematic treatment of refractory cardiac rejection is being evaluated in an ongoing FDA-monitored, open-label rescue study. Patients entered in this trial are those with an ongoing rejection unresponsive to intravenous steroids and/or polyclonal or monoclonal antibodies. All qualifying rejection episodes are International Society for Heart and Lung Transplantation (ISHLT) grade 3A or greater with lesser grades eligible for entry only if accompanied by hemodynamic compromise. Similarly, an open-label rescue study for lung transplant patients with refractory acute or chronic rejection is underway. The acute rejection must be biopsy proven to be ISHLT grade A2 or greater and chronic rejection must be proven by pathology and pulmonary function tests consistent with early bronchiolitis obliterans. Both of these rescue studies involve a photopheresis treatment frequency of 2 consecutive days per week for 4 weeks, and if clinical improvement is noted, continued treatment at 2-week and then monthly intervals is allowed. While there has been only limited anecdotal experience in the past with photo-
2249
pheresis in the prevention or treatment of graft-versus-host disease (GVHD) in bone marrow transplant recipients, an open-label rescue trial of patients with refractory chronic GVHD is currently underway. The patient must have failed to respond to corticosteroids and have GVHD with onset greater than 2 months after transplantation. At least one histologically diagnosed finding and one clinical feature must be present at the time of entry into the study. Histologic findings include a liver, skin, or mucosal biopsy consistent with chronic GVHD or histologically confirmed bronchiolitis obliterans. Clinical findings include skin thickening, sclerosis, hyper/hypopigmentation, or ulceration; joint contracture or fascial thickening; oral ulcerations; or unexplained diarrhea. Other clinical areas of interest for future studies include prophylactic photopheresis to prevent acute and/or chronic rejection in lung and small bowel transplantation in which current results with conventional immunosuppressants have been disappointing. Studies aimed at preventing and/or treating acute cellular and/or chronic vascular rejection; the effect on short- and long-term graft survival; the potential of the therapy to have beneficial antiviral (ie, anti-CMV) effects; and the effect on pretransplant sensitized patients (especially in renal transplantation) are potential areas to explore in all types of solid organ transplantation. Finally, potential improvements in the current design of the disposable photopheresis system circuit to allow a lower extracorporeal volume (which would allow future studies in the pediatric population), a shorter treatment time, and a decrease in the cost of treatments, would be highly desirable. Perhaps of greatest importance to the future of this immunomodulating technology is the characterization and isolation of the transplant recipient’s immune response to the treatment. There are various theories3,12–15 regarding the potential mechanisms involved including generation of CD8 positive clonotypic T cells, increased expression and/or recognition of immunogenic peptides in HLA clefts, inhibition of second signal transmission from antigen presenting cells, and production of cytokines by the extracorporeally treated leukocytes. Future experimental and clinical work will need to establish the optimal treatment frequency and duration required to maintain a beneficial immunologic effect. The subsequent determination of the minimal frequency and duration of required treatments will be particularly important from a cost-containment viewpoint. Potential synergy with other immunoregulatory techniques (such as plasmapheresis or intravenous immunoglobulin infusion) or immunoregulatory agents (such as alpha and gamma interferon, tumor necrosis factor, and IL-12), that have been used experimentally in the treatment of autoimmune diseases and cutaneous T-cell lymphoma,16 need to be investigated in transplantation. Studies involving the effect of photopheresis on tolerance induction and microchimerism will also be of interest. The current studies underway as well as future experimental and clinical work should help to define the long-term role of this novel, safe, and nontoxic
2250
immune modifying technology in the transplantation setting. REFERENCES 1. Gasparro F, Dall’Amico R, Goldminz D, et al: Yale J Biol Med 62:579, 1989 2. Rook A, Cohen J, Lessin S, et al: Derm Clin 11:339, 1993 3. Perez M, Edelson R, Laroche L, et al: J Invest Dermatol 92:669, 1989 4. Pepino P, Berger C, Fuzesi L, et al: Eur Surg Res 21:105, 1989 5. Rose E, Barr M, Xu H, et al: J Heart Lung Transplant 11:746, 1992 6. Costanzo-Nordin M, Hubbell E, O’Sullivan E, et al: Circulation 86:242, 1992 7. Rose E, Pepino P, Barr M, et al: J Heart Lung Transplant 11:S120, 1992
BARR 8. Barr M, McLaughlin S, Murphy M, et al: Transplant Proc 27:1993, 1995 9. Meiser B, Kur F, Reichenspurner H, et al: Transplantation 57:563, 1994 10. Dall’Amico R, Livi U, Milano A, et al: Transplantation 60:45, 1995 11. Knobler R, Trautinger F, Graninger W, et al: J Am Acad Dermatol 28:580, 1993 12. Lider O, Reshef T, Beraud E, et al: Science 239:181, 1988 13. Berger C, Perez M, Laroche L, et al: J Invest Dermatol 94:52, 1990 14. Heald P, Kim H, Perez M, et al: J Clin Apheresis 10:144, 1995 15. Edelson R, Perez M, Heald P, et al: In DeVita V, Hellman S, Rosenberg S (eds): Biologic Therapy of Cancer. Philadelphia: JB Lippincott; 1994, p 1 16. Wolfe J, Lessin S, Singh A, et al: Artific Organs 18:888, 1994