- Email: [email protected]
Ocular Graft vs. Host Disease
Cellular Mediators Ocular Graft vs. Host Disease STELLA K. KIM, MD
ABSTRACT Acute graft vs host disease (GVHD) is thought to be mainly a Th1 inflammatory-mediated process, whereas chronic GVHD involves primarily Th2 inflammation. To elucidate new strategies for the treatment and prevention of ocular GVHD, it is important to understand the pathophysiologic connection between systemic and organ-specific acute and chronic GVHD. The two types of inflammatory processes, however, represent only a part of a highly intricate, complex disorder. Studies to further understand the inflammatory profile of ocular GVHD are ongoing. KEY WORDS graft vs host disease, inflammation, Th1, Th2, transplantation
I. INTRODUCTION
cular graft versus host disease (GVHD) is a manifestation of systemic GVHD in patients after allogeneic stem cell transplantation to treat their hematologic or solid organ malignancies, immunological disorders, or blood dyscrasias. GVHD remains one of the major complications and limitations of successful blood and marrow transplantation. Unlike graft rejection in solid organ transplantations, in which the host immune system rejects the donor tissue, graft vs. host disease involves the donor immune cells recognizing host tissue as foreign, resulting in clinical manifestations, such as rash (skin);
O
Accepted for publication June 2005. From the Section of Ophthalmology, Department of Head and Neck Surgery, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA. The author has no proprietary interest in any product or concept discussed in this article. Single copy reprint requests to: Stella K. Kim, MD (address below). Corresponding author: Stella K. Kim, MD, Section of Ophthalmology, Department of Head and Neck Surgery, UT MD Anderson Cancer Center, 1515 Holcombe Blvd. #441, Houston, TX 77030. Tel. 713-563-0854. Fax 713794-4992. [email protected] Abbreviations are printed in boldface where they first appear with their definitions.
©2005 Ethis Communications, Inc. The Ocular Surface ISSN: 15420124. Kim S. Ocular graft vs. host disease. 2005;3(4):S177-S179.
dry mouth, nausea and diarrhea (upper and lower gastrointestinal [GI] tract); liver function abnormalities (bile duct); restrictive pulmonary conditions; and a myriad of ocular entities, including keratoconjunctivitis sicca, meibomian gland dysfunction, pseudomembranous conjunctivitis, and corneal epithelial sloughing. To understand the clinical manifestations and pathophysiology of organ specific GVHD (i.e., ocular GVHD), it is important to review the literature on systemic GVHD. The topic of GVHD in transplant immunology is vast and complex. Acute and chronic GVHD are briefly summarized below. II. BACKGROUND AND PATHOPHYSIOLOGY OF SYSTEMIC GVHD
The terminology of GVHD is largely divided into acute or chronic events. The grading system of GVHD is a subject of much debate, with an ongoing national consensus group to address the grading metrics. The current grading system makes the distinction between acute and chronic GVHD based on when GVHD occurs, i.e., before or after day-100 post-bone marrow transplant (BMT), respectively. The clinical manifestations of acute GVHD include desquamation of skin with bullae formation, severe bile duct injury with choleostasis, and extensive loss of GI crypt epithelium.1 Features of chronic GVHD are more complex and resemble mixed autoimmune-like diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma, with a wide range of clinical features, including excessive fibrosis, stenosis, atrophy of tissue, especially in the skin, obliteration of pulmonary tissues, and ocular sicca syndrome.2 Chronic GVHD may result from the progression of acute GVHD, recur after acute GVHD has resolved, or manifest de novo without previous history of acute GVHD. Chronic GVHD patients may experience a flare-up, typically at the time of taper or discontinuation of systemic immunosuppression, with clinical features of an acute or chronic pattern of GVHD. Pathophysiology of acute and chronic GVHD is complex, but, for the most part, acute GVHD is thought to be mainly a Th1 inflammatory-mediated process, whereas chronic GVHD involves primarily Th2 inflammation. Pathophysiology of acute GVHD, described as a “cytokine storm,” is a process that can be summarized in three phases: allo-antigen presentation, donor T cell expansion and differentiation, and cytotoxic effects of end-organ targets. The first phase starts with the pre-transplantation regimen, with
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OCULAR GRAFT VS. HOST DISEASE / Kim ARTICLE OUTLINE I. II. III. IV.
Introduction Background and pathophysiology of systemic GVHD Ocular GVHD Conclusion
chemotherapy and/or radiotherapy, which induce damage of the host tissue, with release of inflammatory cytokines such as TNF-α and interleukin (IL)-1. This enhances myosin heavy chain (MHC) protein expression and allo-antigen processing by host antigen presenting cells, which are recognized by the donor T cells, resulting in T cell proliferation and differentiation, with more IL-2 and interferon (IFN)-γ production. These cytokines, along with chemokines, recruit mononuclear cells and macrophages, which increase the cytokine loop with TNF-α and IL-1, enhancing the expansion of cytotoxic lymphocytes and natural killer (NK) cells. Effector cells and cytotoxic T cells, also recruited by inflammatory chemokines and cytokines, induce a cytotoxic process at the target organs, resulting in apoptosis (the histopathological hallmark of GVHD) in keratinocytes of the skin, crypts of the GI tract, bile ducts of the liver, and epithelium of conjunctiva.3 In the chronic form of GVHD, it is thought that Th2 inflammation predominates with lymphoproliferation and IL-4 and IL-10 production. From the pre-transplantation conditioning and/or from acute GVHD, resulting thymic atrophy is thought to occur, leading to dysfunction of negative selection process, which normally keeps self-reactive lymphocytes in check. Expansion of these auto-reactive T cells (CD4+ Th2) promotes activation of auto-reactive B cells, which results in the production of auto-antibodies. Culmination of these events is decreased self-tolerance and ongoing inflammatory reaction to various organs.4 The link between the pathophysiology of systemic GVHD and organ-specific GVHD is the subject of multidiscipline studies and remains yet to be fully understood. III. OCULAR GVHD All layers of ocular tissue can be affected by ocular GVHD, from the eye lid to the choroid. Lids may show classic skin GVHD with severe telangiectatic vessels, thickened lid margins, and hyper/hypopigmentations. The meibomian glands may be severely affected with glandular drop-out, contributing to the ocular surface disease. The most commonly observed ocular GVHD is conjunctival inflammatory disease and lacrimal gland dysfunction with dry eye syndrome.5 The staging system of ocular GVHD currently extends only to conjunctival disease: Stage I as hyperemia; Stage II as hyperemia with serosanguinous chemosis; Stage III as pseudomembranous conjunctivitis; and Stage IV as membranous/pseudomembranous conjunctivitis plus corneal epithelial sloughing.6 While conjunctival disease and lacrimal gland dysfunction can both be observed before or S-178
after day-100 post transplantation, the severe form of conjunctival disease is typically considered as “acute pattern” ocular GVHD, while lacrimal gland dysfunction/ keratoconjunctivitis sicca syndrome is associated with the chronic GVHD spectrum. Conjunctival GVHD, including pseudomembranous conjunctivitis, has been suggested as a marker for severity of systemic GVHD.6 Earlier descriptions of conjunctival GVHD histological specimens as lymphocyte exocytosis, satellitosis, and epithelial cell necrosis7-9 may all be consistent with apoptosis, the hallmark of GHVD. These studies have suggested that conjunctival biopsy may be helpful in demonstrating the presence of low grade GVHD, particularly in patients for whom GVHD is localized only to ocular tissues.7 Histopathological specimens of pseudomembranous conjunctivitis with infiltrations of predominantly donor T cells and mononuclear cells with NK cell markers have been observed.10,11 Nonspecific inflammatory responses on histopathologic evaluation have also been reported.12 Conjunctival antigen presenting cells (MHCII-positive dendritic cells) are found in abundance in the substantia propria and in the epithelium of conjunctiva (Langerhans cells) in the palpebral conjunctiva and in the fornix, which correspond to the areas where pseudomembranous conjunctivitis in acute pattern ocular GVHD manifest. In the acute systemic GVHD process, activation and subsequent cascade of the inflammatory process occurs as a “cytokine storm.” A similar process may cause localized reaction at the level of the palpebral conjunctiva, resulting in clinical manifestations of denuded conjunctival epithelium, ulceration, and pseudomembranous conjunctivitis. Current experience with pseudomembranous conjunctivitis and its management at MD Anderson Cancer Center suggests the presence of pro-inflammatory milieu in the pseudomembranous tissue. Our recent review of 14 patients with pseudomembranous ocular GVHD showed that with careful removal of the pseudomembrane along with topical immunosuppression may prevent the progression to stage IV ocular GVHD and result in less cicatricial conjunctival scarring. Current studies are ongoing to understand the inflammatory process of conjunctival GVHD. Lacrimal gland dysfunction/keratoconjunctivitis sicca (KCS) occurs both in the acute and chronic setting of GVHD. Earlier histopathological observation of lacrimal glands of GVHD patients shows “lacrimal gland stasis” with distended ductules and obliteration of lumina, similar to bile duct damage seen in liver GVHD.8,9,13 Immunohistochemical and ultrastructural studies of lacrimal glands from chronic ocular GVHD patients have been described.14,15 Increased fibroblasts, excessive fibrosis in the extracellular matrix, and multilayered basal lamina of the ducts, vessels, and lobules in the lacrimal glands have been observed.14 The other study strongly suggests that the periductal region in the lacrimal gland may be the primary site for CD4+ and CD8+ T cell activation and that a subset of fibroblasts may function as antigen-presenting
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cells in this region.15 The findings in these two studies have been summarized in a comprehensive review, in which the pathogenic pathway of lacrimal gland in ocular GVHD was postulated with fibroblasts being the sentinel cell population responsible for both immunosurveillance function and fibrosis production. It has been reported that Type 2 cytokines may play a role in fibrosis17 in other tissues. Its connection to lacrimal gland dysfunction in ocular GVHD still needs to be established. IV. CONCLUSION Understanding the pathophysiologic connection between systemic and organ-specific acute and chronic GVHD is crucial in elucidating new strategies for the treatment and prevention of ocular GVHD. The type of ocular inflammation must be considered in the context of the Th1/Th2 inflammation of acute and chronic systemic GVHD, respectively. The two types of inflammatory processes, however, represent only part of a highly intricate, complex disorder. Efforts to further elucidate the inflammatory profile of ocular GVHD are ongoing. REFERENCES 1. Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic graftversus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004;10:178-85 2. Sale GE, Shulman HM, Hackman RC. Pathology of hematopoietic cell transplantation, in Thomas ED, Blume KG, Forman SJ (eds). Hematopoietic cell transplantation. 1998, Malden MA, Blackwell Science, 1998, pp 248-63 3. Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol 2003;78:181-7 4. Kansu E. The pathophysiology of chronic graft-versus-host disease. Int J Hematol 2004;79:209-15 5. Ogawa Y, Okamoto S, Wakui M, et al. Dry eye after haematopoietic stem cell transplantation. Br J Ophthalmol 1999;83:1125-30
6. Jabs DA, Wingard J, Green WR, et al. The eye in bone marrow transplantation. III. Conjunctival graft-vs-host disease. Arch Ophthalmol 1989;107:1343-8 7. West RH, Szer J, Pedersen JS. Ocular surface and lacrimal disturbances in chronic graft-versus-host disease: the role of conjunctival biopsy. Aust N Z J Ophthalmol 1991;19:187-91 8. Sale GE, Shulman HM, Schubert MM, et al. Oral and ophthalmic pathology of graft versus host disease in man: predictive value of the lip biopsy. Hum Pathol 1981;12:1022-30 9. Jack MK, Jack GM, Sale GE, et al. Ocular manifestations of graft-vs-host disease. Arch Ophthalmol 1983;101:1080-4 10. Saito T, Shinagawa K, Takenaka K, et al. Ocular manifestation of acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. Int J Hematol 2002;75:332-4 11. Janin A, Facon T, Castier P, et al. Pseudomembranous conjunctivitis following bone marrow transplantation: immunopathological and ultrastructural study of one case. Hum Pathol 1996;27:307-9. 12. Hirst LW, Jabs DA, Tutschka PJ, et al. The eye in bone marrow transplantation. I. Clinical study. Arch Ophthalmol 1983;101:580-4 13. Jabs DA, Hirst LW, Green WR, et al. The eye in bone marrow transplantation. II. Histopathology. Arch Ophthalmol 1983;101:585-90 14. Ogawa Y, Yamazaaki K, Kuwana M, et al. A significant role of stromal fibroblasts in rapidly progressive dry eye in patients with chronic GVHD. Invest Ophthalmol Vis Sci 2001;42:111-9 15. Ogawa Y, Kuwana M, Yamasaki K, et al. Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease. Invest Ophthalmol Vis Sci 2003;44:1888-96 16. OgawaY, Kuwana M. Dry eye as a major complication associated with chronic graft-versus-host disease after hematopoietic stem cell transplantation. Cornea 2003;22(7 Suppl):S19-27 17. Sime PJ, O’Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol 2001;99: 308-19
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ABSTRACT Acute graft vs host disease (GVHD) is thought to be mainly a Th1 inflammatory-mediated process, whereas chronic GVHD involves primarily Th2 inflammation. To elucidate new strategies for the treatment and prevention of ocular GVHD, it is important to understand the pathophysiologic connection between systemic and organ-specific acute and chronic GVHD. The two types of inflammatory processes, however, represent only a part of a highly intricate, complex disorder. Studies to further understand the inflammatory profile of ocular GVHD are ongoing. KEY WORDS graft vs host disease, inflammation, Th1, Th2, transplantation
I. INTRODUCTION
cular graft versus host disease (GVHD) is a manifestation of systemic GVHD in patients after allogeneic stem cell transplantation to treat their hematologic or solid organ malignancies, immunological disorders, or blood dyscrasias. GVHD remains one of the major complications and limitations of successful blood and marrow transplantation. Unlike graft rejection in solid organ transplantations, in which the host immune system rejects the donor tissue, graft vs. host disease involves the donor immune cells recognizing host tissue as foreign, resulting in clinical manifestations, such as rash (skin);
O
Accepted for publication June 2005. From the Section of Ophthalmology, Department of Head and Neck Surgery, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA. The author has no proprietary interest in any product or concept discussed in this article. Single copy reprint requests to: Stella K. Kim, MD (address below). Corresponding author: Stella K. Kim, MD, Section of Ophthalmology, Department of Head and Neck Surgery, UT MD Anderson Cancer Center, 1515 Holcombe Blvd. #441, Houston, TX 77030. Tel. 713-563-0854. Fax 713794-4992. [email protected] Abbreviations are printed in boldface where they first appear with their definitions.
©2005 Ethis Communications, Inc. The Ocular Surface ISSN: 15420124. Kim S. Ocular graft vs. host disease. 2005;3(4):S177-S179.
dry mouth, nausea and diarrhea (upper and lower gastrointestinal [GI] tract); liver function abnormalities (bile duct); restrictive pulmonary conditions; and a myriad of ocular entities, including keratoconjunctivitis sicca, meibomian gland dysfunction, pseudomembranous conjunctivitis, and corneal epithelial sloughing. To understand the clinical manifestations and pathophysiology of organ specific GVHD (i.e., ocular GVHD), it is important to review the literature on systemic GVHD. The topic of GVHD in transplant immunology is vast and complex. Acute and chronic GVHD are briefly summarized below. II. BACKGROUND AND PATHOPHYSIOLOGY OF SYSTEMIC GVHD
The terminology of GVHD is largely divided into acute or chronic events. The grading system of GVHD is a subject of much debate, with an ongoing national consensus group to address the grading metrics. The current grading system makes the distinction between acute and chronic GVHD based on when GVHD occurs, i.e., before or after day-100 post-bone marrow transplant (BMT), respectively. The clinical manifestations of acute GVHD include desquamation of skin with bullae formation, severe bile duct injury with choleostasis, and extensive loss of GI crypt epithelium.1 Features of chronic GVHD are more complex and resemble mixed autoimmune-like diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma, with a wide range of clinical features, including excessive fibrosis, stenosis, atrophy of tissue, especially in the skin, obliteration of pulmonary tissues, and ocular sicca syndrome.2 Chronic GVHD may result from the progression of acute GVHD, recur after acute GVHD has resolved, or manifest de novo without previous history of acute GVHD. Chronic GVHD patients may experience a flare-up, typically at the time of taper or discontinuation of systemic immunosuppression, with clinical features of an acute or chronic pattern of GVHD. Pathophysiology of acute and chronic GVHD is complex, but, for the most part, acute GVHD is thought to be mainly a Th1 inflammatory-mediated process, whereas chronic GVHD involves primarily Th2 inflammation. Pathophysiology of acute GVHD, described as a “cytokine storm,” is a process that can be summarized in three phases: allo-antigen presentation, donor T cell expansion and differentiation, and cytotoxic effects of end-organ targets. The first phase starts with the pre-transplantation regimen, with
THE OCULAR SURFACE / OCTOBER 2005, VOL. 3, NO. 4 / SUPPLEMENT
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OCULAR GRAFT VS. HOST DISEASE / Kim ARTICLE OUTLINE I. II. III. IV.
Introduction Background and pathophysiology of systemic GVHD Ocular GVHD Conclusion
chemotherapy and/or radiotherapy, which induce damage of the host tissue, with release of inflammatory cytokines such as TNF-α and interleukin (IL)-1. This enhances myosin heavy chain (MHC) protein expression and allo-antigen processing by host antigen presenting cells, which are recognized by the donor T cells, resulting in T cell proliferation and differentiation, with more IL-2 and interferon (IFN)-γ production. These cytokines, along with chemokines, recruit mononuclear cells and macrophages, which increase the cytokine loop with TNF-α and IL-1, enhancing the expansion of cytotoxic lymphocytes and natural killer (NK) cells. Effector cells and cytotoxic T cells, also recruited by inflammatory chemokines and cytokines, induce a cytotoxic process at the target organs, resulting in apoptosis (the histopathological hallmark of GVHD) in keratinocytes of the skin, crypts of the GI tract, bile ducts of the liver, and epithelium of conjunctiva.3 In the chronic form of GVHD, it is thought that Th2 inflammation predominates with lymphoproliferation and IL-4 and IL-10 production. From the pre-transplantation conditioning and/or from acute GVHD, resulting thymic atrophy is thought to occur, leading to dysfunction of negative selection process, which normally keeps self-reactive lymphocytes in check. Expansion of these auto-reactive T cells (CD4+ Th2) promotes activation of auto-reactive B cells, which results in the production of auto-antibodies. Culmination of these events is decreased self-tolerance and ongoing inflammatory reaction to various organs.4 The link between the pathophysiology of systemic GVHD and organ-specific GVHD is the subject of multidiscipline studies and remains yet to be fully understood. III. OCULAR GVHD All layers of ocular tissue can be affected by ocular GVHD, from the eye lid to the choroid. Lids may show classic skin GVHD with severe telangiectatic vessels, thickened lid margins, and hyper/hypopigmentations. The meibomian glands may be severely affected with glandular drop-out, contributing to the ocular surface disease. The most commonly observed ocular GVHD is conjunctival inflammatory disease and lacrimal gland dysfunction with dry eye syndrome.5 The staging system of ocular GVHD currently extends only to conjunctival disease: Stage I as hyperemia; Stage II as hyperemia with serosanguinous chemosis; Stage III as pseudomembranous conjunctivitis; and Stage IV as membranous/pseudomembranous conjunctivitis plus corneal epithelial sloughing.6 While conjunctival disease and lacrimal gland dysfunction can both be observed before or S-178
after day-100 post transplantation, the severe form of conjunctival disease is typically considered as “acute pattern” ocular GVHD, while lacrimal gland dysfunction/ keratoconjunctivitis sicca syndrome is associated with the chronic GVHD spectrum. Conjunctival GVHD, including pseudomembranous conjunctivitis, has been suggested as a marker for severity of systemic GVHD.6 Earlier descriptions of conjunctival GVHD histological specimens as lymphocyte exocytosis, satellitosis, and epithelial cell necrosis7-9 may all be consistent with apoptosis, the hallmark of GHVD. These studies have suggested that conjunctival biopsy may be helpful in demonstrating the presence of low grade GVHD, particularly in patients for whom GVHD is localized only to ocular tissues.7 Histopathological specimens of pseudomembranous conjunctivitis with infiltrations of predominantly donor T cells and mononuclear cells with NK cell markers have been observed.10,11 Nonspecific inflammatory responses on histopathologic evaluation have also been reported.12 Conjunctival antigen presenting cells (MHCII-positive dendritic cells) are found in abundance in the substantia propria and in the epithelium of conjunctiva (Langerhans cells) in the palpebral conjunctiva and in the fornix, which correspond to the areas where pseudomembranous conjunctivitis in acute pattern ocular GVHD manifest. In the acute systemic GVHD process, activation and subsequent cascade of the inflammatory process occurs as a “cytokine storm.” A similar process may cause localized reaction at the level of the palpebral conjunctiva, resulting in clinical manifestations of denuded conjunctival epithelium, ulceration, and pseudomembranous conjunctivitis. Current experience with pseudomembranous conjunctivitis and its management at MD Anderson Cancer Center suggests the presence of pro-inflammatory milieu in the pseudomembranous tissue. Our recent review of 14 patients with pseudomembranous ocular GVHD showed that with careful removal of the pseudomembrane along with topical immunosuppression may prevent the progression to stage IV ocular GVHD and result in less cicatricial conjunctival scarring. Current studies are ongoing to understand the inflammatory process of conjunctival GVHD. Lacrimal gland dysfunction/keratoconjunctivitis sicca (KCS) occurs both in the acute and chronic setting of GVHD. Earlier histopathological observation of lacrimal glands of GVHD patients shows “lacrimal gland stasis” with distended ductules and obliteration of lumina, similar to bile duct damage seen in liver GVHD.8,9,13 Immunohistochemical and ultrastructural studies of lacrimal glands from chronic ocular GVHD patients have been described.14,15 Increased fibroblasts, excessive fibrosis in the extracellular matrix, and multilayered basal lamina of the ducts, vessels, and lobules in the lacrimal glands have been observed.14 The other study strongly suggests that the periductal region in the lacrimal gland may be the primary site for CD4+ and CD8+ T cell activation and that a subset of fibroblasts may function as antigen-presenting
THE OCULAR SURFACE / OCTOBER 2005, VOL. 3, NO. 4 / SUPPLEMENT
OCULAR GRAFT VS. HOST DISEASE / Kim
cells in this region.15 The findings in these two studies have been summarized in a comprehensive review, in which the pathogenic pathway of lacrimal gland in ocular GVHD was postulated with fibroblasts being the sentinel cell population responsible for both immunosurveillance function and fibrosis production. It has been reported that Type 2 cytokines may play a role in fibrosis17 in other tissues. Its connection to lacrimal gland dysfunction in ocular GVHD still needs to be established. IV. CONCLUSION Understanding the pathophysiologic connection between systemic and organ-specific acute and chronic GVHD is crucial in elucidating new strategies for the treatment and prevention of ocular GVHD. The type of ocular inflammation must be considered in the context of the Th1/Th2 inflammation of acute and chronic systemic GVHD, respectively. The two types of inflammatory processes, however, represent only part of a highly intricate, complex disorder. Efforts to further elucidate the inflammatory profile of ocular GVHD are ongoing. REFERENCES 1. Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic graftversus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004;10:178-85 2. Sale GE, Shulman HM, Hackman RC. Pathology of hematopoietic cell transplantation, in Thomas ED, Blume KG, Forman SJ (eds). Hematopoietic cell transplantation. 1998, Malden MA, Blackwell Science, 1998, pp 248-63 3. Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol 2003;78:181-7 4. Kansu E. The pathophysiology of chronic graft-versus-host disease. Int J Hematol 2004;79:209-15 5. Ogawa Y, Okamoto S, Wakui M, et al. Dry eye after haematopoietic stem cell transplantation. Br J Ophthalmol 1999;83:1125-30
6. Jabs DA, Wingard J, Green WR, et al. The eye in bone marrow transplantation. III. Conjunctival graft-vs-host disease. Arch Ophthalmol 1989;107:1343-8 7. West RH, Szer J, Pedersen JS. Ocular surface and lacrimal disturbances in chronic graft-versus-host disease: the role of conjunctival biopsy. Aust N Z J Ophthalmol 1991;19:187-91 8. Sale GE, Shulman HM, Schubert MM, et al. Oral and ophthalmic pathology of graft versus host disease in man: predictive value of the lip biopsy. Hum Pathol 1981;12:1022-30 9. Jack MK, Jack GM, Sale GE, et al. Ocular manifestations of graft-vs-host disease. Arch Ophthalmol 1983;101:1080-4 10. Saito T, Shinagawa K, Takenaka K, et al. Ocular manifestation of acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. Int J Hematol 2002;75:332-4 11. Janin A, Facon T, Castier P, et al. Pseudomembranous conjunctivitis following bone marrow transplantation: immunopathological and ultrastructural study of one case. Hum Pathol 1996;27:307-9. 12. Hirst LW, Jabs DA, Tutschka PJ, et al. The eye in bone marrow transplantation. I. Clinical study. Arch Ophthalmol 1983;101:580-4 13. Jabs DA, Hirst LW, Green WR, et al. The eye in bone marrow transplantation. II. Histopathology. Arch Ophthalmol 1983;101:585-90 14. Ogawa Y, Yamazaaki K, Kuwana M, et al. A significant role of stromal fibroblasts in rapidly progressive dry eye in patients with chronic GVHD. Invest Ophthalmol Vis Sci 2001;42:111-9 15. Ogawa Y, Kuwana M, Yamasaki K, et al. Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease. Invest Ophthalmol Vis Sci 2003;44:1888-96 16. OgawaY, Kuwana M. Dry eye as a major complication associated with chronic graft-versus-host disease after hematopoietic stem cell transplantation. Cornea 2003;22(7 Suppl):S19-27 17. Sime PJ, O’Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol 2001;99: 308-19
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