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Selective immunomodulation in patients with inflammatory bowel disease—future therapy or reality?
The Netherlands
JOURNAL OF MEDICINE ELSEVIER
Netherlands Journal of Medicine 48 (1996) 64 67
Selective immunomodulation in patients with inflammatory bowel disease future therapy or reality? R.A. van Hogezand *, H.W. Verspaget Department of Gastroenterology-Hepatology, UniversityHospital Leiden, Rijnsburgerweg 10, 2333AA Leiden, Netherlands
Abstract Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor- a (TNF-a). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administred cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating ,cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-lra) competitively binds to the 1L-1 receptor located on several lymphocytes. Treatment of animals with IL-lra has been successful and clinical trials using recombinant IL-lra are underway in IBD. Antibodies against aIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of c~-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-a shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNF-a were excellent. Keywords: Inflammatory bowel disease; Crohn's disease; Ulcerative colitis; Immunosuppressive therapy; Cytokines; Anti-CD4; Anti-TNF-a
1. Introduction In ulcerative colitis a n d C r o h n ' s d i s e a s e the bowel m u c o s a is inflamed. In ulcerative colitis
* Corresponding author.
this i n f l a m m a t i o n is c h a r a c t e r i z e d by an extensive infiltration o f the m u c o s a by n e u t r o p h i l s and m o n o n u c l e a r cells, resulting in crypt abscesses. In C r o h n ' s d i s e a s e the most typical histological feat u r e is e p i t h e l i o i d g r a n u l o m a . A l t h o u g h t h e s e inf l a m m a t o r y bowel d i s e a s e s ( I B D ) have b e e n t r e a t e d relatively successful with all kinds o f
0300-2977/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSD1 0300-2977(95)00091-7
R.A. van Hogezand, H. IV.. Verspaget / Netherlands Journal of Medicine 48 (1996) 64-67
anti-inflammatory drugs for a long time now, it is remarkable that our knowledge of the aetiology and pathogenesis of the inflammation is still insufficient. It is thought that some antigen is the trigger which induces immune reactions of the putative target cell (i.e., colonic mucosa cell), but the nature of this antigen has not so far been elucidated. Whatever mechanism initiates and maintains the intestinal inflammation, there are sufficient data that prove a vigorous local mucosal immune response. This reaction is associated with mobilization and induction of macrophages and lymphocytes in the gut mucosa and is accompanied by tissue oedema, vascular proliferation, and ulceration. It has been demonstrated that enhanced uptake of endotoxin from the gut lumen contributes to the systemic complications of ulcerative colitis and Crohn's disease. Active disease, surgical manipulation, and colonoscopy all lead to endotoxaemia [1-3]. The high concentration of endotoxin in the bowel lumen and the excess of endotoxinresponsive cells (e.g., macrophages) in areas of mucosal inflammation are suggested to play a role in the induction and control of the mucosal inflammation. Endotoxins are membrane constituents of aerobic or anaerobic gram-negative bacteria. In theory an antigen-presenting cell, like macrophages, forms a complex with endotoxinderived peptides as antigen. When this complex is presented at the surface of the cell, T-helper lymphocytes are attracted, activated and start to produce endogenous proteins (so-called cytokines). For inflammatory bowel diseases the most important cytokines identified are interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), gamma-interferon (G1FN), and tumor necrosis factor-a (TNF-a). The uncontrolled release of cytokines is thought to contribute to the inflammatory response, resulting in tissue damage. In the past, cytokines were thought to be specific in their actions. In the last few years, however, several studies have demonstrated a pleiotropism and redundancy within the cytokine network. In active Crohn's disease CD4 + T-helper lymphocytes are often detected to be increased. The lymphocytic CD4 and CD8 (from T-suppressor/
65
cytotoxic lymphocytes) molecules act as adhesion molecules for, respectively, major histocompatibility complex (MHC) class II and I on the antigen-presenting cell. In this way CD4 and CD8 are needed to form the interaction between the M H C - a n t i g e n complex on the antigen-presenting cell and the lymphocytes.
2. Possible therapeutic considerations
Cyclosporine, since 1987 used for treatment of inflammatory bowel disease, reduces the production of cytokines at the level of the T-helper cell. It downregulates the cellular and humoral immunity by a specific receptor-mediated process, resulting in decreased IL-2 and gamma-interferon production with reduced T-helper cell function and reduced antigen presentation. Cyclosporine is widely used in the field of transplantation. Although substantial inhibition of the production of cytokines results in improvement of the inflammatory process in Crohn's disease and ulcerative colitis, this treatment is not very selective. Moreover, cyclosporine has many side-effects (headache, hypertension, gingival hyperplasia, increased inflammation, liver and kidney disturbances) which reduce its therapeutic applications. In acute ulcerative colitis 11 out of 14 patients responded immediately to cyclosporine after failure of 10 days treatment with steroids [4]. Improvement of ulcerative colitis with intravenous cyclosporine (4 m g / k g ) was demonstrated by the same group. Nine out of 11 patients resistent to 7 days intravenous steroids improved, whereas no patient in the placebo group improved [5]. Furthermore, two open studies demonstrated that rectal administration of cyclosporine (250 or 350 m g / d a y ) could be effective for distal ulcerative colitis [6,7]. However, in a placebo-controlled double-blind study no benefit was shown [8]. In Crohn's disease 3 months treatment was found to be effective compared to placebo [9], but 1 year later, when the medication was discontinued for half a year, no difference was seen [10]. Another study, with patients in remission and on a lowdose cyclosporine, demonstrated that relapses often occurred [11]. Intravenous cyclosporine, how-
66
R.A. van Hogezand, H.W. Verspaget /Netherlands Journal of Medicine 48 (1996) 64-67
ever, was found to be effective in an open study involving 5 patients with Crohn's disease in which 10 out of 12 fistulae, unresponsive before to many ways of treatment, closed [12]. The novel immunosuppressant FKS06 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine [13]. IL-1 is a polypeptide protein which plays an important role in the pathogenesis of inflammatory bowel disease because it is a potent activator of B- and T-cells. The production of IL-1 by peripheral blood mononuclear cells and lamina propria mononuclear cells has been reported to be increased in IBD and correlates with the degree of inflammation and clinical activity. Furthermore, IL-1 seems to increase with relapse of Crohn's disease [10]. A naturally occurring receptor antagonist of IL-1 (IL-lra) is produced by monocytes and macrophages, which also produce IL-1. I L - l r a competitively binds to the IL-1 receptor located on T- and B-cells, mesenchymal cells, macrophages and neutrophils. T r e a t m e n t with I L - l r a has been evaluated in animals only. Rabbits pretreated with I L - l r a showed a considerable decrease in colonic tissue inflammation and necrosis induced by IL-1 [14-16]. Clinical trials using recombinant I L - l r a are underway to investigate a new direction of therapy in IBD. IL-2 has an important role in acute and chronic inflammatory diseases. Its function is to stimulate growth of T-cells, to induce T-cell cytotoxicity and to induce proliferation and differentiation of antibody producing B-cells. IL-2 interacts with specific T-cell IL-2 receptors ( a and /3), which are not only present on the cell surface but are also present in a soluble form in serum (slL-2r). The role of sIL-2r is unclear but it binds IL-2 and competes with T-cells for the available IL-2 and thereby has an immunoregulatory function. Use of antibodies against a l L - 2 r has proved to be of benefit in animal studies and in transplantation studies. To date, no study has been reported on IBD patients. In some studies gamma-interferon was found to be increased in inflammatory bowel disease, while in others it was found to be decreased. Gamma-interferon has an important role in con-
trolling the development of an immune response by stimulating antigen presentation. Gamma-interferon has not been found to be of use in IBD. In general, interferon elicits a protective reaction after viral infection of a cell. The use of interferon, particularly a-IFN, might be effective in some patients with Crohn's disease [17]. Specific monoclonal antibodies against CD4 may be suitable to modulate the immune response in vivo. Studies with anti-CD4 antibodies in patients with ulcerative colitis and Crohn's disease showed a dose-related immune suppressive effect in patients with active disease [18,19]. T N F - a is found in increased amounts in the mucosa and stools of patients with inflammatory bowel disease. Particularly high levels are found in patients with Crohn's disease. T N F - a shares many of the proinflammatory activities of IL-1. In a preliminary study the response of a patient with Crohn's disease treated with chimeric antibodies to T N F - a was excellent but lasted for only 2 - 3 months [20]. In another open trial 10 patients with Crohn's disease were treated successfully as illustrated by the decreased activity indices in all patients [21]. In ulcerative colitis the effects are found to be less impressive.
3. Conclusion
In the future, more selective immunomodulation can be expected for the treatment of inflammatory bowel diseases. Cyclosporine decreases the production of all cytokines, with an acute effect on the disease activity, but it has many side-effects. More selective inhibition of the individual cytokines is still experimental, although promising preliminary results have been obtained with IL-lra, antibodies against aIL-2r, a-interferon and anti-TNF-o~.
References
[1] Colin R, Grancher T, Lemeland J-F. Recherche d'une endotoxin~mie dans les ent~rocolites inflammatoire cryptog~niques. Gastroent6rol Clin Biol 1979;3:15-19. [2] Palmer KR, Duerden BI, Holdsworth CD. Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut 1980;21:851-854.
R.A. l:an Hogezand, H.W. Verspaget / Netherlands Journal of Medicine 48 (1996) 64-67
[3] Kiss A, Ferenci W, Graninger W. Endotoxemia following colonoscopy. Endoscopy 1983;15:24-26. [4] Lichtiger S, Present DH. Preliminary report: cyclosporine in treatment of severe active ulcerative colitis. Lancet 1990;336:16-19. [5] Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-1845. [6] Sandborn W J, Tremaine WJ, Schroeder KW, et al. A randomized, double-blind, placebo-controlled trial of cyclosporin enemas for mildly to moderately active leftsided ulcerative colitis. Gastroenterology 1993;104:775 (Abstract). [7] Winter TA, Dalton HR, Merrett MN, Campbell A, Jewell DP. Cyclosporin A retention enemas in refractory distal ulcerative colitis and 'pouchitis'. Scand J Gastroenterol 1993;28:701-704. [8] Sandborn WJ, Tremaine WJ, Schroeder KW, Steiner BL, Batts KP, Lawson GM. Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis. Am J Gastroenterol 1993;88:640-645. [9] Brynskov J, Freund L, Rasmussen SN, et al. A placebocontrolled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:845-850. [10] Brynskov J, Freund L, Norby Rasmussen S, et al. Final report on a placebo-controlled, double-blind, randomized, multicentre trial of cyclosporin treatment in active chronic Crohn's disease. Scand J Gastroenterol 1991;26: 689-695. [11] Lobo AJ, Juby LD, Rothwell J, Poole TW, Axon AT. Long-term treatment of Crohn's disease with cyclosporine: the effect of a very low dose on maintenance of remission. J Clin Gastroenterol 1991;13:42-45.
67
[12] Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646-649. [13] Macleod AM, Thomson AW. FK506: an immunosuppressant for the 1990s? Lancet 1991;337:25-27. [14] Dinarello CA, Thompson RC. Blocking IL-I: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 1991;12:404-410. [15] Cominelli F, Nast CC, Duchini A, Lee M. Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis. Gastroenterology 1992;103:65-71. [16] Thompson RC, Dripps DJ, Eisenberg SP. Interleukin-1 receptor antagonist (IL-lra) as a probe and as a treatment for IL-1 mediated disease. Int J Immunopharmacol 1992;14:475-480. [17] Wirth HP, Zala G, Meyenberger C, Jost R, Ammann R, Munch R. Alpha-interferon therapy in Crohn's disease: initial clinical results. Schweiz Med Wochenschr 1993;123:1384-1388. [18] Emmrich J, Seyfarth M, Fleig WE, Emmrich F. Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody. Lancet 1991;338:570-571. [19] Stronkhorst A, Tytgat GN, van Deventer SJ. CD4 antibody treatment in Crohn's disease. Scand J Gastroenterol Suppl 1992;194:61-65. [20] Derkx B, Taminiau J, Radema S, et al. Tumor necrosis factor antibody treatment in Crohn's disease. Lancet 1993;342:173-174. [21] van Dullemen HM, van Deventer SJM, Hommes DW, et al. Treatment of Crohn's disease with anti-Tumor Necrosis Factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129-135.
JOURNAL OF MEDICINE ELSEVIER
Netherlands Journal of Medicine 48 (1996) 64 67
Selective immunomodulation in patients with inflammatory bowel disease future therapy or reality? R.A. van Hogezand *, H.W. Verspaget Department of Gastroenterology-Hepatology, UniversityHospital Leiden, Rijnsburgerweg 10, 2333AA Leiden, Netherlands
Abstract Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohn's disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor- a (TNF-a). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administred cyclosporine is able to improve the disease activity in ulcerative colitis and Crohn's disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating ,cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-lra) competitively binds to the 1L-1 receptor located on several lymphocytes. Treatment of animals with IL-lra has been successful and clinical trials using recombinant IL-lra are underway in IBD. Antibodies against aIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of c~-interferon seems to be effective in some patients with Crohn's disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohn's disease. TNF-a shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohn's disease, the effects of the administration of antibodies to TNF-a were excellent. Keywords: Inflammatory bowel disease; Crohn's disease; Ulcerative colitis; Immunosuppressive therapy; Cytokines; Anti-CD4; Anti-TNF-a
1. Introduction In ulcerative colitis a n d C r o h n ' s d i s e a s e the bowel m u c o s a is inflamed. In ulcerative colitis
* Corresponding author.
this i n f l a m m a t i o n is c h a r a c t e r i z e d by an extensive infiltration o f the m u c o s a by n e u t r o p h i l s and m o n o n u c l e a r cells, resulting in crypt abscesses. In C r o h n ' s d i s e a s e the most typical histological feat u r e is e p i t h e l i o i d g r a n u l o m a . A l t h o u g h t h e s e inf l a m m a t o r y bowel d i s e a s e s ( I B D ) have b e e n t r e a t e d relatively successful with all kinds o f
0300-2977/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSD1 0300-2977(95)00091-7
R.A. van Hogezand, H. IV.. Verspaget / Netherlands Journal of Medicine 48 (1996) 64-67
anti-inflammatory drugs for a long time now, it is remarkable that our knowledge of the aetiology and pathogenesis of the inflammation is still insufficient. It is thought that some antigen is the trigger which induces immune reactions of the putative target cell (i.e., colonic mucosa cell), but the nature of this antigen has not so far been elucidated. Whatever mechanism initiates and maintains the intestinal inflammation, there are sufficient data that prove a vigorous local mucosal immune response. This reaction is associated with mobilization and induction of macrophages and lymphocytes in the gut mucosa and is accompanied by tissue oedema, vascular proliferation, and ulceration. It has been demonstrated that enhanced uptake of endotoxin from the gut lumen contributes to the systemic complications of ulcerative colitis and Crohn's disease. Active disease, surgical manipulation, and colonoscopy all lead to endotoxaemia [1-3]. The high concentration of endotoxin in the bowel lumen and the excess of endotoxinresponsive cells (e.g., macrophages) in areas of mucosal inflammation are suggested to play a role in the induction and control of the mucosal inflammation. Endotoxins are membrane constituents of aerobic or anaerobic gram-negative bacteria. In theory an antigen-presenting cell, like macrophages, forms a complex with endotoxinderived peptides as antigen. When this complex is presented at the surface of the cell, T-helper lymphocytes are attracted, activated and start to produce endogenous proteins (so-called cytokines). For inflammatory bowel diseases the most important cytokines identified are interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), gamma-interferon (G1FN), and tumor necrosis factor-a (TNF-a). The uncontrolled release of cytokines is thought to contribute to the inflammatory response, resulting in tissue damage. In the past, cytokines were thought to be specific in their actions. In the last few years, however, several studies have demonstrated a pleiotropism and redundancy within the cytokine network. In active Crohn's disease CD4 + T-helper lymphocytes are often detected to be increased. The lymphocytic CD4 and CD8 (from T-suppressor/
65
cytotoxic lymphocytes) molecules act as adhesion molecules for, respectively, major histocompatibility complex (MHC) class II and I on the antigen-presenting cell. In this way CD4 and CD8 are needed to form the interaction between the M H C - a n t i g e n complex on the antigen-presenting cell and the lymphocytes.
2. Possible therapeutic considerations
Cyclosporine, since 1987 used for treatment of inflammatory bowel disease, reduces the production of cytokines at the level of the T-helper cell. It downregulates the cellular and humoral immunity by a specific receptor-mediated process, resulting in decreased IL-2 and gamma-interferon production with reduced T-helper cell function and reduced antigen presentation. Cyclosporine is widely used in the field of transplantation. Although substantial inhibition of the production of cytokines results in improvement of the inflammatory process in Crohn's disease and ulcerative colitis, this treatment is not very selective. Moreover, cyclosporine has many side-effects (headache, hypertension, gingival hyperplasia, increased inflammation, liver and kidney disturbances) which reduce its therapeutic applications. In acute ulcerative colitis 11 out of 14 patients responded immediately to cyclosporine after failure of 10 days treatment with steroids [4]. Improvement of ulcerative colitis with intravenous cyclosporine (4 m g / k g ) was demonstrated by the same group. Nine out of 11 patients resistent to 7 days intravenous steroids improved, whereas no patient in the placebo group improved [5]. Furthermore, two open studies demonstrated that rectal administration of cyclosporine (250 or 350 m g / d a y ) could be effective for distal ulcerative colitis [6,7]. However, in a placebo-controlled double-blind study no benefit was shown [8]. In Crohn's disease 3 months treatment was found to be effective compared to placebo [9], but 1 year later, when the medication was discontinued for half a year, no difference was seen [10]. Another study, with patients in remission and on a lowdose cyclosporine, demonstrated that relapses often occurred [11]. Intravenous cyclosporine, how-
66
R.A. van Hogezand, H.W. Verspaget /Netherlands Journal of Medicine 48 (1996) 64-67
ever, was found to be effective in an open study involving 5 patients with Crohn's disease in which 10 out of 12 fistulae, unresponsive before to many ways of treatment, closed [12]. The novel immunosuppressant FKS06 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine [13]. IL-1 is a polypeptide protein which plays an important role in the pathogenesis of inflammatory bowel disease because it is a potent activator of B- and T-cells. The production of IL-1 by peripheral blood mononuclear cells and lamina propria mononuclear cells has been reported to be increased in IBD and correlates with the degree of inflammation and clinical activity. Furthermore, IL-1 seems to increase with relapse of Crohn's disease [10]. A naturally occurring receptor antagonist of IL-1 (IL-lra) is produced by monocytes and macrophages, which also produce IL-1. I L - l r a competitively binds to the IL-1 receptor located on T- and B-cells, mesenchymal cells, macrophages and neutrophils. T r e a t m e n t with I L - l r a has been evaluated in animals only. Rabbits pretreated with I L - l r a showed a considerable decrease in colonic tissue inflammation and necrosis induced by IL-1 [14-16]. Clinical trials using recombinant I L - l r a are underway to investigate a new direction of therapy in IBD. IL-2 has an important role in acute and chronic inflammatory diseases. Its function is to stimulate growth of T-cells, to induce T-cell cytotoxicity and to induce proliferation and differentiation of antibody producing B-cells. IL-2 interacts with specific T-cell IL-2 receptors ( a and /3), which are not only present on the cell surface but are also present in a soluble form in serum (slL-2r). The role of sIL-2r is unclear but it binds IL-2 and competes with T-cells for the available IL-2 and thereby has an immunoregulatory function. Use of antibodies against a l L - 2 r has proved to be of benefit in animal studies and in transplantation studies. To date, no study has been reported on IBD patients. In some studies gamma-interferon was found to be increased in inflammatory bowel disease, while in others it was found to be decreased. Gamma-interferon has an important role in con-
trolling the development of an immune response by stimulating antigen presentation. Gamma-interferon has not been found to be of use in IBD. In general, interferon elicits a protective reaction after viral infection of a cell. The use of interferon, particularly a-IFN, might be effective in some patients with Crohn's disease [17]. Specific monoclonal antibodies against CD4 may be suitable to modulate the immune response in vivo. Studies with anti-CD4 antibodies in patients with ulcerative colitis and Crohn's disease showed a dose-related immune suppressive effect in patients with active disease [18,19]. T N F - a is found in increased amounts in the mucosa and stools of patients with inflammatory bowel disease. Particularly high levels are found in patients with Crohn's disease. T N F - a shares many of the proinflammatory activities of IL-1. In a preliminary study the response of a patient with Crohn's disease treated with chimeric antibodies to T N F - a was excellent but lasted for only 2 - 3 months [20]. In another open trial 10 patients with Crohn's disease were treated successfully as illustrated by the decreased activity indices in all patients [21]. In ulcerative colitis the effects are found to be less impressive.
3. Conclusion
In the future, more selective immunomodulation can be expected for the treatment of inflammatory bowel diseases. Cyclosporine decreases the production of all cytokines, with an acute effect on the disease activity, but it has many side-effects. More selective inhibition of the individual cytokines is still experimental, although promising preliminary results have been obtained with IL-lra, antibodies against aIL-2r, a-interferon and anti-TNF-o~.
References
[1] Colin R, Grancher T, Lemeland J-F. Recherche d'une endotoxin~mie dans les ent~rocolites inflammatoire cryptog~niques. Gastroent6rol Clin Biol 1979;3:15-19. [2] Palmer KR, Duerden BI, Holdsworth CD. Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut 1980;21:851-854.
R.A. l:an Hogezand, H.W. Verspaget / Netherlands Journal of Medicine 48 (1996) 64-67
[3] Kiss A, Ferenci W, Graninger W. Endotoxemia following colonoscopy. Endoscopy 1983;15:24-26. [4] Lichtiger S, Present DH. Preliminary report: cyclosporine in treatment of severe active ulcerative colitis. Lancet 1990;336:16-19. [5] Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-1845. [6] Sandborn W J, Tremaine WJ, Schroeder KW, et al. A randomized, double-blind, placebo-controlled trial of cyclosporin enemas for mildly to moderately active leftsided ulcerative colitis. Gastroenterology 1993;104:775 (Abstract). [7] Winter TA, Dalton HR, Merrett MN, Campbell A, Jewell DP. Cyclosporin A retention enemas in refractory distal ulcerative colitis and 'pouchitis'. Scand J Gastroenterol 1993;28:701-704. [8] Sandborn WJ, Tremaine WJ, Schroeder KW, Steiner BL, Batts KP, Lawson GM. Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis. Am J Gastroenterol 1993;88:640-645. [9] Brynskov J, Freund L, Rasmussen SN, et al. A placebocontrolled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:845-850. [10] Brynskov J, Freund L, Norby Rasmussen S, et al. Final report on a placebo-controlled, double-blind, randomized, multicentre trial of cyclosporin treatment in active chronic Crohn's disease. Scand J Gastroenterol 1991;26: 689-695. [11] Lobo AJ, Juby LD, Rothwell J, Poole TW, Axon AT. Long-term treatment of Crohn's disease with cyclosporine: the effect of a very low dose on maintenance of remission. J Clin Gastroenterol 1991;13:42-45.
67
[12] Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646-649. [13] Macleod AM, Thomson AW. FK506: an immunosuppressant for the 1990s? Lancet 1991;337:25-27. [14] Dinarello CA, Thompson RC. Blocking IL-I: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 1991;12:404-410. [15] Cominelli F, Nast CC, Duchini A, Lee M. Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis. Gastroenterology 1992;103:65-71. [16] Thompson RC, Dripps DJ, Eisenberg SP. Interleukin-1 receptor antagonist (IL-lra) as a probe and as a treatment for IL-1 mediated disease. Int J Immunopharmacol 1992;14:475-480. [17] Wirth HP, Zala G, Meyenberger C, Jost R, Ammann R, Munch R. Alpha-interferon therapy in Crohn's disease: initial clinical results. Schweiz Med Wochenschr 1993;123:1384-1388. [18] Emmrich J, Seyfarth M, Fleig WE, Emmrich F. Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody. Lancet 1991;338:570-571. [19] Stronkhorst A, Tytgat GN, van Deventer SJ. CD4 antibody treatment in Crohn's disease. Scand J Gastroenterol Suppl 1992;194:61-65. [20] Derkx B, Taminiau J, Radema S, et al. Tumor necrosis factor antibody treatment in Crohn's disease. Lancet 1993;342:173-174. [21] van Dullemen HM, van Deventer SJM, Hommes DW, et al. Treatment of Crohn's disease with anti-Tumor Necrosis Factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129-135.