Cytokine-Based Therapies for Crohn's Disease — New Paradigms
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《新英格兰医药杂志》
Crohn's disease is one of two idiopathic inflammatory bowel diseases that affect approximately 1 million people in North America. Despite important advances in diagnosis and treatment in recent years, the underlying cause of the disease remains unclear. As a result, the available therapies are not curative and may pose a substantial risk of side effects. A current theory regarding the pathogenesis of Crohn's disease suggests that there is an overly aggressive immune response against commensal bacteria in a genetically predisposed person. In this context, the activation of lymphocytes and the overexpression of inflammatory cytokines represent a common effector mechanism leading to chronic intestinal inflammation. This theory has led to the development of several novel therapeutic agents that specifically block the production of key cytokines in patients with Crohn's disease, including the first successful therapeutic biologic agent, infliximab. However, this anti–tumor necrosis factor (TNF-) agent is far from being universally applicable and has raised as many questions as it has provided solutions.
The classic paradigm for cytokine involvement in the pathogenesis of Crohn's disease focuses on type 1 helper T-cell (Th1) cytokines, such as TNF-, interleukin-12, and interferon-, which are thought to have a primary role in initiating the disease process. Conversely, type 2 helper T-cell (Th2) cytokines, such as interleukin-4 and interleukin-13, are considered to have a more prominent role in ulcerative colitis, the other idiopathic inflammatory bowel disease. However, mounting evidence suggests that this classic Th1–Th2 paradigm may be overly simplistic, and the hypothesis that these two pathways are always mutually exclusive has recently been challenged. Immunologic models are therefore now being proposed that involve both clusters of cytokines. Furthermore, individual cytokines may have diverse, and even opposing, functions in different clinical and immunologic scenarios. This is particularly true in Crohn's disease, in which the inflammatory process appears to develop in two distinct phases — an initial, inductive phase and an effector phase characterized by chronic inflammation. Both Th1 and Th2 pathways may be involved in each phase, either concomitantly or sequentially. Taking into account all these observations, some have suggested that a distinction between innate and adaptive cytokines may be more accurate than the distinction between Th1 and Th2 cytokines (see Figure).1
Figure. Working Hypothesis Regarding the Role of Cytokines in the Pathogenesis of Crohn's Disease.
When the mucosal immune system in patients predisposed to the development of Crohn's disease is first exposed to an initiating antigenic stimulus, a dysregulated and overly aggressive cytokine-mediated T-cell response is mounted. Cytokines involved in innate immune responses, such as tumor necrosis factor (TNF-), interleukin-1, interleukin-6, and possibly interleukins 12 and 18, may play a key role in this phase. Once CD4+ T cells are activated, effector cytokines involved in the adaptive immune response, including TNF- and interferon-, as well as interleukins 4 and 13, mediate the effector phase of the intestinal inflammatory response. Novel cytokines such as TL1A and interleukins 23, 27, and 31 may also contribute to the effector phase. BP denotes binding protein, ra receptor antagonist, ROS reactive oxygen species, and LT lymphotoxin.
The traditional viewpoint has been that Crohn's disease results from a dysregulated response by the acquired immune system. However, recent evidence indicates that the innate immune system may be equally important, especially in the inductive phase of disease. First, it is now recognized that defects in epithelial barrier function, such as those that are present in a variety of animal models, lead to intestinal inflammation. Second, cells of the innate immune system are important producers of cytokines such as interleukin-1, TNF-, and interleukin-6, which have important inflammatory effects within the intestinal mucosa. Finally, the first gene that has been described as conferring susceptibility to Crohn's disease encodes an intracellular protein (i.e., NOD2/CARD15) used by cells of the innate immune system to sense the presence of bacterial products through the activation of nuclear factor-B–dependent cytokines. Despite the fact that the precise function of NOD2/CARD15 during intestinal inflammation remains unclear, these observations have led to the intriguing hypothesis that Crohn's disease may be initiated by a defective innate immune response, with decreased production of nuclear factor-B–dependent cytokines in response to commensal bacteria. In this regard, it could be argued that blocking certain cytokines in the initial phases of Crohn's disease may not be beneficial and could actually aggravate the existing disease process.
Several inflammatory cytokines have been targeted for therapeutic intervention in Crohn's disease; these include interleukins 1, 2, 6, 12, and 18, interferon-, and TNF- (see Figure). The most successful example of such intervention to date has been the use of anti–TNF- therapy in patients with refractory and fistulizing Crohn's disease. In this issue of the Journal, Mannon et al. (pages 2069–2079) report on the safety of an anti–interleukin-12 monoclonal antibody administered subcutaneously for seven weeks. Despite the small number of patients included in this study, the authors describe a significant clinical response in the group that received the higher dose (3 mg per kilogram of body weight).
Like TNF-, interleukin-12 is an important Th1-polarizing cytokine that is strongly implicated in the pathogenesis of Crohn's disease. In addition to neutralizing the inflammatory effects of TNF- and interleukin-12, anti–TNF- and anti–interleukin-12 therapies appear to share a common mechanism of inducing apoptosis in activated lymphocytes that have infiltrated the intestinal mucosa.2,3,4 Protection of intestinal epithelial cells from apoptosis has also been suggested as a potential antiinflammatory mechanism of anti–TNF- therapy in Crohn's disease.3
Given these early successes, more cytokines are rapidly being identified as potential therapeutic targets; among them are interleukins 18, 23, 27, and 31, as well as TL1A. In addition, the therapeutic potential of cytokines that belong to the traditional Th2-polarizing class is being evaluated; this group includes interleukins 4 and 13, for which there is increasing evidence of a potential inflammatory role, particularly in small intestinal disease.
Cytokine blockade with monoclonal antibodies, fusion proteins, and receptor antagonists remains an attractive method of immunomodulation in Crohn's disease. However, important questions remain regarding the safety of long-term treatment, especially since classic Th1 cytokines are important in combating infections. The reactivation of latent tuberculosis in patients who have received anti–TNF- therapy is an example of the potential for harm due to the long-term suppression of host responses against certain infectious agents.5 The long-term risk of malignancy with anti-cytokine therapeutics in general and the possibility that anti–interleukin-12 therapy, in particular, may reactivate asthma also need to be considered. In addition, on the basis of our improved understanding of the complex pathogenesis of Crohn's disease — in particular, the existence of multiple phases of disease — the realization is developing that blocking certain cytokines may be detrimental, rather than beneficial, in some situations. The inability of anti–TNF- treatment (infliximab) to induce remission in a substantial percentage of patients with Crohn's disease could indicate that non-Th1 effector pathways or a different disease phase may predominate in these patients. An effective treatment strategy for such patients might therefore involve the blockade of multiple cytokines in order to intervene in several pathways. Despite these limitations, the development of anticytokine therapies as part of the physician's armamentarium is an important staging post on the road to a cure for Crohn's disease.
Source Information
From the Health Sciences Center, University of Virginia, Charlottesville.
References
Reuter BK, Pizarro TT. The role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? Eur J Immunol 2004;34:2347-2355.
Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 2003;124:1774-1785.
Marini M, Bamias G, Rivera-Nieves J, et al. TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc Natl Acad Sci U S A 2003;100:8366-8371.
Fuss IJ, Marth T, Neurath MF, Pearlstein GR, Jain A, Strober W. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology 1999;117:1078-1088.
Tuberculosis associated with blocking agents against tumor necrosis factor-alpha -- California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:683-686.(Fabio Cominelli, M.D., Ph)
The classic paradigm for cytokine involvement in the pathogenesis of Crohn's disease focuses on type 1 helper T-cell (Th1) cytokines, such as TNF-, interleukin-12, and interferon-, which are thought to have a primary role in initiating the disease process. Conversely, type 2 helper T-cell (Th2) cytokines, such as interleukin-4 and interleukin-13, are considered to have a more prominent role in ulcerative colitis, the other idiopathic inflammatory bowel disease. However, mounting evidence suggests that this classic Th1–Th2 paradigm may be overly simplistic, and the hypothesis that these two pathways are always mutually exclusive has recently been challenged. Immunologic models are therefore now being proposed that involve both clusters of cytokines. Furthermore, individual cytokines may have diverse, and even opposing, functions in different clinical and immunologic scenarios. This is particularly true in Crohn's disease, in which the inflammatory process appears to develop in two distinct phases — an initial, inductive phase and an effector phase characterized by chronic inflammation. Both Th1 and Th2 pathways may be involved in each phase, either concomitantly or sequentially. Taking into account all these observations, some have suggested that a distinction between innate and adaptive cytokines may be more accurate than the distinction between Th1 and Th2 cytokines (see Figure).1
Figure. Working Hypothesis Regarding the Role of Cytokines in the Pathogenesis of Crohn's Disease.
When the mucosal immune system in patients predisposed to the development of Crohn's disease is first exposed to an initiating antigenic stimulus, a dysregulated and overly aggressive cytokine-mediated T-cell response is mounted. Cytokines involved in innate immune responses, such as tumor necrosis factor (TNF-), interleukin-1, interleukin-6, and possibly interleukins 12 and 18, may play a key role in this phase. Once CD4+ T cells are activated, effector cytokines involved in the adaptive immune response, including TNF- and interferon-, as well as interleukins 4 and 13, mediate the effector phase of the intestinal inflammatory response. Novel cytokines such as TL1A and interleukins 23, 27, and 31 may also contribute to the effector phase. BP denotes binding protein, ra receptor antagonist, ROS reactive oxygen species, and LT lymphotoxin.
The traditional viewpoint has been that Crohn's disease results from a dysregulated response by the acquired immune system. However, recent evidence indicates that the innate immune system may be equally important, especially in the inductive phase of disease. First, it is now recognized that defects in epithelial barrier function, such as those that are present in a variety of animal models, lead to intestinal inflammation. Second, cells of the innate immune system are important producers of cytokines such as interleukin-1, TNF-, and interleukin-6, which have important inflammatory effects within the intestinal mucosa. Finally, the first gene that has been described as conferring susceptibility to Crohn's disease encodes an intracellular protein (i.e., NOD2/CARD15) used by cells of the innate immune system to sense the presence of bacterial products through the activation of nuclear factor-B–dependent cytokines. Despite the fact that the precise function of NOD2/CARD15 during intestinal inflammation remains unclear, these observations have led to the intriguing hypothesis that Crohn's disease may be initiated by a defective innate immune response, with decreased production of nuclear factor-B–dependent cytokines in response to commensal bacteria. In this regard, it could be argued that blocking certain cytokines in the initial phases of Crohn's disease may not be beneficial and could actually aggravate the existing disease process.
Several inflammatory cytokines have been targeted for therapeutic intervention in Crohn's disease; these include interleukins 1, 2, 6, 12, and 18, interferon-, and TNF- (see Figure). The most successful example of such intervention to date has been the use of anti–TNF- therapy in patients with refractory and fistulizing Crohn's disease. In this issue of the Journal, Mannon et al. (pages 2069–2079) report on the safety of an anti–interleukin-12 monoclonal antibody administered subcutaneously for seven weeks. Despite the small number of patients included in this study, the authors describe a significant clinical response in the group that received the higher dose (3 mg per kilogram of body weight).
Like TNF-, interleukin-12 is an important Th1-polarizing cytokine that is strongly implicated in the pathogenesis of Crohn's disease. In addition to neutralizing the inflammatory effects of TNF- and interleukin-12, anti–TNF- and anti–interleukin-12 therapies appear to share a common mechanism of inducing apoptosis in activated lymphocytes that have infiltrated the intestinal mucosa.2,3,4 Protection of intestinal epithelial cells from apoptosis has also been suggested as a potential antiinflammatory mechanism of anti–TNF- therapy in Crohn's disease.3
Given these early successes, more cytokines are rapidly being identified as potential therapeutic targets; among them are interleukins 18, 23, 27, and 31, as well as TL1A. In addition, the therapeutic potential of cytokines that belong to the traditional Th2-polarizing class is being evaluated; this group includes interleukins 4 and 13, for which there is increasing evidence of a potential inflammatory role, particularly in small intestinal disease.
Cytokine blockade with monoclonal antibodies, fusion proteins, and receptor antagonists remains an attractive method of immunomodulation in Crohn's disease. However, important questions remain regarding the safety of long-term treatment, especially since classic Th1 cytokines are important in combating infections. The reactivation of latent tuberculosis in patients who have received anti–TNF- therapy is an example of the potential for harm due to the long-term suppression of host responses against certain infectious agents.5 The long-term risk of malignancy with anti-cytokine therapeutics in general and the possibility that anti–interleukin-12 therapy, in particular, may reactivate asthma also need to be considered. In addition, on the basis of our improved understanding of the complex pathogenesis of Crohn's disease — in particular, the existence of multiple phases of disease — the realization is developing that blocking certain cytokines may be detrimental, rather than beneficial, in some situations. The inability of anti–TNF- treatment (infliximab) to induce remission in a substantial percentage of patients with Crohn's disease could indicate that non-Th1 effector pathways or a different disease phase may predominate in these patients. An effective treatment strategy for such patients might therefore involve the blockade of multiple cytokines in order to intervene in several pathways. Despite these limitations, the development of anticytokine therapies as part of the physician's armamentarium is an important staging post on the road to a cure for Crohn's disease.
Source Information
From the Health Sciences Center, University of Virginia, Charlottesville.
References
Reuter BK, Pizarro TT. The role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? Eur J Immunol 2004;34:2347-2355.
Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 2003;124:1774-1785.
Marini M, Bamias G, Rivera-Nieves J, et al. TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc Natl Acad Sci U S A 2003;100:8366-8371.
Fuss IJ, Marth T, Neurath MF, Pearlstein GR, Jain A, Strober W. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology 1999;117:1078-1088.
Tuberculosis associated with blocking agents against tumor necrosis factor-alpha -- California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:683-686.(Fabio Cominelli, M.D., Ph)