- Email: [email protected]
The role of immunocytes in acute and chronic pancreatitis: When friends turn into enemies
626 EDITORIALS
by TNB-induced colitis in rats. However, because none of the strategies used so far including the central blockade of the interleukin-1 receptor and the inhibition of prostaglandin or serotonin synthesis were able to restore normal feeding on the first days after TNB administration, simultaneous alterations of multiple pathways regulating food intake must come into play. This field of investigation would therefore benefit from recent advances made in the identification of several new hypothalamic neuropeptides and receptors that affect food intake and energy balance.16 Unraveling how these molecules, their neuronal systems, and receptors are modulated during colitis and their relationship to serotonin may provide additional insights to the circuitries between peripheral immune signals and the hypothalamic effector pathways in anorexia. YVETTE TACHE´ Digestive Diseases Division Digestive Diseases Research Center Department of Medicine, University of California Los Angeles, California
References 1. Gee MI, Grace MG, Wensel RH, Sherbaniuk R, Thomson AB. Protein-energy malnutrition in gastroenterology outpatients: increased risk in Crohn’s disease. J Am Diet Assoc 1985;85:1466– 1474. 2. Rigaud D, Angel LA, Cerf M, Carduner MJ, Melchior JC, Sautier C, Rene E, Apfelbaum M, Mignon M. Mechanisms of decreased food intake during weight loss in adult Crohn’s disease patients without obvious malabsorption. Am J Clin Nutr 1994;60:775– 781. 3. McCartney S, Ballinger A. Growth failure in inflammatory bowel disease (editorial). Nutrition 1999;15:169–171. 4. Ballinger A. Divergency of leptin response in intestinal inflammation. Gut 1999;44:588–589.
GASTROENTEROLOGY Vol. 118, No. 3
5. Kim HS, Berstad A. Experimental colitis in animal models. Scand J Gastroenterol 1992;27:529–537. 6. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 1995; 109:1344–1367. 7. McHugh KJ, Weingarten HP, Keenan C, Wallace JL, Collins SM. On the suppression of food intake in experimental models of colitis in the rat. Am J Physiol 1993;264:R871–R876. 8. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 1989;96:795–803. 9. McHugh K, Castonguay TW, Collins SM, Weingarten HP. Characterization of suppression of food intake following acute colon inflammation in the rat. Am J Physiol 1993;265:R1001–R1005. 10. Larson SJ, Collins SM, Weingarten HP. Dissociation of temperature changes and anorexia after experimental colitis and LPS administration in rats. Am J Physiol 1996;271:R967–R972. 11. McHugh KJ, Collins SM, Weingarten HP. Central interleukin-1 receptors contribute to suppression of feeding after acute colitis in the rat. Am J Physiol 1994;266:R1659–R1663. 12. Barbier M, Cherbut C, Aube AC, Blottiere HM, Galmiche JP. Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 1998;43:783–790. 13. Leibowitz SF, Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 1998;44:851–864. 14. Ballinger A, El-Haj T, Perrett D, Turvill J, Obeid O, Dryden S, Williams G, Farthing MJG. The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis. Gastroenterology 2000;118:544–553. 15. Koprowska M, Krotewicz M, Romaniuk A, Strzelczuk M, Wieczorek M. Behavioral and neurochemical alterations evoked by p-chlorophenylalanine application in rats examined in the lightdark crossing test. Acta Neurobiol Exp (Warsz) 1999;59:15–22. 16. Lawrence CB, Turnbull AV, Rothwell NJ. Hypothalamic control of feeding. Curr Opin Neurobiol 1999;9:778–783. Address requests for reprints to: Yvette Tache ´, Ph.D., Department of Medicine, UCLA School of Medicine, 11301 Wilshire Boulevard, Los Angeles, California 90073-1792. e-mail: [email protected]; fax: (310) 268-4963. r 2000 by the American Gastroenterological Association 0016-5085/00/$10.00
The Role of Immunocytes in Acute and Chronic Pancreatitis: When Friends Turn Into Enemies See articles on pages 573 and 582.
he articles by Okazaki1 and Demols2 and their colleagues in this issue of GASTROENTEROLOGY assign immunocytes an important role in both acute and chronic pancreatitis. In acute pancreatitis, they act as the principal contributor to the acute systemic inflammatory response that determines early severity. In cases of autoimmune chronic pancreatitis, they are identified as
T
the cells responsible for perpetuating the chronic inflammatory process of the pancreatic gland. In acute pancreatitis, although late sepsis-related deaths resulting from infection of pancreatic necrosis can be countered by antibiotic treatment, some early deaths seem to be unavoidable because of serious multiorgan dysfunction.3 Moderating the overwhelming severe systemic inflammatory response has been found to prevent early complications and reduce severity in early acute pancreatitis.4 As a result, considerable effort has been put
March 2000
into developing treatments to do just this,5 as exemplified by anti–tumor necrosis factor ␣ antibody,6 interleukin (IL)-1 receptor antagonist,7 anti–intercellular adhesion molecule (ICAM),8 IL-10,9 or anti-CD3 antibodies.10 In view of its possible clinical impact, studying the role of immunocytes (e.g., granulocytes, macrophages, and lymphocytes) in pancreatitis is at present one of the most important topics in pancreatitis research. Devising new approaches to treat pancreatitis by influencing the complex immune response may soon further improve survival in this frequent and still dangerous disease.
Immunocytes in Acute Pancreatitis Polymorphonuclear (PMN)-granulocytes play a central role in the development of local, as well as systemic, complications of severe acute pancreatitis. Infiltrating PMNs, in part through production of oxygen free radicals, aggravate acute pancreatitis and contribute to local destruction and systemic complications.11 Recognition of the role of PMN-granulocytes has led to strategies to deplete PMN-granulocytes as therapeutic intervention in acute pancreatitis. Infiltrating neutrophils and macrophages are responsible for the intrapancreatic IL-1 production during acute pancreatitis, and their elimination by PMN antiserum significantly decreases the severity of pancreatic tissue destruction.12 Depletion of neutrophil granulocytes ameliorates the severity of acute pancreatitis in the early course of the disease and is associated with an increase in apoptotic cells in the later stage of experimental acute pancreatitis.13 Furthermore, pretreatment with antineutrophil serum completely prevents lung injury in acute pancreatitis14 and significantly reduced vacuolization in cerulein-induced pancreatitis in rats.13 There is also a large body of direct and indirect evidence for the involvement of lymphocytes in acute pancreatitis. If an overwhelming severe early systemic inflammatory response triggers pancreatic and systemic complications in acute pancreatitis, and immunocytes are responsible for these, anti-inflammatory therapy should reduce systemic complications. Indeed, a variety of agents including anti-ICAM antibodies,8 IL-10,9,15 the interleukin-1 receptor antagonist,16 anti-inflammatory peptides (e.g., CNI-149317), use of the recombinant plateletactivating factor acetyl hydrolase rPAF-AH,18 corticosteroids,19 anti-CD3 antibodies, and the calcineurin antagonist FK50610 have been found to reduce severity in early acute pancreatitis. Of interest, Russian groups used immunosuppressants
EDITORIALS 627
such as cyclophosphamide in the treatment of severe acute pancreatitis as early as the 1970s.20 Recently, our group has substantiated the pathophysiological basis of this treatment strategy by showing that the absence of active lymphocytes in mice with severe combined immunodeficiency disease is associated with reduced severity of acute pancreatitis.21 In acute pancreatitis, the number and ratio of CD4⫹ and CD8⫹ lymphocytes change dramatically, suggesting that T lymphocytes, primarily CD4⫹ T-helper (Th) cells may be involved in the events leading to severe pancreatitis.22 The IL-2 receptor is expressed mainly on activated lymphocytes, and in severe acute pancreatitis, the amount of soluble IL-2 receptor is increased in serum22 consistently. It has been suggested that an inadequate Th1 response in early acute pancreatitis is associated with systemic but not local complications.23 The determination of blood Th1 cytokines in early acute pancreatitis has been found to predict severity,24 and lymphocyteassociated cytokines may be suitable markers for monitoring acute pancreatitis.23 Conversely, attenuating IL-2– mediated Th1 activation, e.g., by a calcineurin inhibitor, typically reduces the severity of experimental acute pancreatitis.10 Paradoxically, an increased susceptibility to sepsis has been observed in a later stage of the disease, presumed to result from impaired immune function. Ironically, it could also be overcome by treatment with IL-2.25 Presumably, acute pancreatitis is, immunologically speaking, a two-phase disease: an initial hyperstimulation of the immune system, which causes early systemic complications, is followed by a variably long period of immune suppression, increasing the susceptibility for bacterial or fungal infection and, consequently, morbidity caused by sepsis. Other experimental and clinical observations lend further support to the inference that lymphocytes can play an important role in the pathophysiology of pancreatitis. Aged major histocompatibility complex (MHC) II–deficient mice ‘‘spontaneously’’ develop an immunebased pancreatitis with a selective loss of exocrine cells and functions, providing a model of immune-based pancreatic injury.26 Clinically, acute immune-related pancreatitis is a frequent finding in acute graft-versus-host disease in children with severe combined immunodeficiency and DiGeorge syndrome.27 The observation that the drug pyritinol may cause immune-related pancreatitis by activating CD4/CD8 lymphocytes28 is further indicative of the role lymphocytes play in acute pancreatitis, as is the suggested involvement of abnormal lymphocyte responsiveness in patients developing acute pancreatitis after renal transplantation.29
628 EDITORIALS
Immunocytes in Chronic Pancreatitis Some recent studies have focused on the role of nonspecific activation of PMN leukocytes locally, and immunocytes belonging to the T-cell family systemically, in chronic pancreatitis. Several groups have characterized the infiltrating lymphocytes present in tissue specimens of chronic pancreatitis.30–32 All investigators found an increased number of infiltrating lymphocytes, and most groups support the hypothesis of an involvement of cell-mediated cytotoxicity in the pathogenesis of chronic pancreatitis, as shown by elevated frequencies of perforin-expressing cells33 or CD8⫹CD103⫹ T cells30 in human chronic pancreatitis. In contrast to this hypothesis of cell-mediated toxicity, Emmerich et al.32 found a more acute inflammatory type of infiltrating lymphocytes in chronic pancreatitis tissue specimens. However, the chronic pancreatitis specimens investigated were not subdivided into idiopathic, alcoholic, or autoimmune chronic pancreatitis, making it impossible to specify and identify a special type of immune cell infiltration in the different types of chronic pancreatitis. The idea of an autoimmune action as the trigger for a subtype of chronic pancreatitis has been proposed for more than 30 years since Sarles first described pancreatitis associated with hypergammaglobulinemia. In the study by Okazaki et al.,1 the authors detected high autoantibodies against lactoferrin, carbonic anhydrase II, and other typical autoimmune targets in the sera of patients with autoimmune pancreatitis. In a detailed analysis of peripheral blood T cells from these patients, they found a Th1 type–mediated immune response, which is characterized by predominant cellular immunity, macrophage activation, cytotoxicity, and support of B-cell function including production of opsonizing and complement-fixing antibodies. These observations support the conclusion that this destructive form of chronic pancreatitis is mediated by autoimmune processes, and that this type of autoimmune pancreatitis clinically responds well to steroid therapy. In conclusion, several studies during the past decade have advanced our understanding of the role of immunocytes in acute and autoimmune chronic pancreatitis, systemically in the former and locally in the latter. The clinical implication of these observations, i.e., the potential utility of immunosuppressive therapy, offers new hope for more effective treatment of these diseases. HANS G. BEGER FRANK GANSAUGE JENS M. MAYER Department of General Surgery University of Ulm Ulm, Germany
GASTROENTEROLOGY Vol. 118, No. 3
References 1. Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, Matsushima Y, Katamura K, Ohmori K, Chiba T. Autoimmunerelated pancreatitis is associated with autoantibodies and Th1/ Th2-type cellular immune response. Gastroenterology 2000;118: 573–581. 2. Demols A, Le Moine O, Desalle F, Quertinmont E, Van Laethem J-L, Devie`re J. CD4⫹ T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology 2000;118: 582–590. 3. Lowham A, Lavelle J, Leese T. Mortality from acute pancreatitis. Int J Pancreatol 1999;25:103–106. 4. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998;175:76–83. 5. Beger HG, Rau B, Mayer J, Pralle U. Natural course of acute pancreatitis. World J Surg 1997;21:130–135. 6. Grewal HP, El Din AM, Gaber L, Kotb M, Gaber O. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti–TNF-alpha polyclonal antibody. Am J Surg 1994;167: 214–219. 7. Tanaka K, Murata A, Uda K, Toda H, Kato T, Hayashida H, Matsuura N, Mori T. Interleukin 1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med 1995;23:901–908. 8. Werner J, Z’graggen K, Fernandez del Castillo C, Lewandrowski K, Compton CC, Warshaw A. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg 1999;229:834–840. 9. Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology 1997;112:960–967. 10. Mayer J, Laine VJO, Kolodziej S, Nevalainen TJ, Storck M, Beger HG. Prevention of early pancreatitis-associated complications by immunomodulatory drugs (abstr). Pancreas 1999;19:43. 11. Poch B, Gansauge F, Rau B, Wittel U, Gansauge S, Nu¨ssler A, Schoenberg MH, Beger HG. The role of polymorphonuclear leukocytes and oxygen-derived free radicals in experimental acute pancreatitis: mediators of local destruction and activators of inflammation. FEBS Lett 1999;461:268–272. 12. Fink GW, Norman J. Intrapancreatic interleukin 1beta gene expression by specific leukocyte populations during acute pancreatitis. J Surg Res 1996;63:369–373. 13. Sandoval D, Gukovskaya AS, Reavey P, Gukovski S, Sisk A, Braquet P, Pandol SJ, Poucell Hatton S. The role of neutrophils and platelet-activating factor in mediating experimental pancreatitis. Gastroenterology 1996;111:1081–1091. 14. Bhatia M, Saluja A, Hofbauer B, Lee HS, Frossard JL, Steer ML. The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis–associated lung injury. Int J Pancreatol 1998;24:77–83. 15. Van Laethem JL, Marchant A, Delvaux A, Goldman M, Robberecht P, Velu T, Deviere J. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology 1995;108: 1917–1922. 16. Norman JG, Franz MG, Fink GS, Messina J, Fabri PJ, Gower WR, Carey LC. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg 1995;221:625–634. 17. Yang J, Denham W, Carter G, Tracey K, Norman J. Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. Hepatology 1998;28:1282–1288. 18. Hofbauer B, Saluja A, Bhatia M, Frossard JL, Lee HS, Bhagat L, Steer ML. Effect of recombinant platelet-activating factor acetyl hydrolase on two models of experimental acute pancreatitis. Gastroenterology 1998;115:1238–1247. 19. Lazar GJ, Lazar G, Duda E, Takacs T, Balogh A, Lonovics J. The
March 2000
20.
21.
22.
23. 24.
25.
26.
27.
effects of glucocorticoids and a glucocorticoid antagonist (RU 38486) on experimental acute pancreatitis in rat. Acta Chir Hung 1997;36:190–191. Shaposhnikov IG, Reshetnikov EA, Miasnikova NA, Kondrateva IE. Role of immunosuppression in the complex treatment of acute pancreatitis. Khirurgiia (Mosk) 1980;1:85–89. Mayer J, Laine VJO, Rau B, Hotz HG, Foitzik T, Nevalainen TJ, Beger HG. Systemic lymphocyte activation modulates the severity of diet-induced acute pancreatitis in mice. Pancreas 1999;19:62– 68. Pezzilli R, Billi P, Gullo L, Beltrandi E, Maldini M, Mancini R, Incorvaia L, Miglioli M. Behavior of serum soluble interleukin-2 receptor, soluble CD8 and soluble CD4 in the early phases of acute pancreatitis. Digestion 1994;55:268–273. Kusske AM, Rongione AJ, Reber HA. Cytokines and acute pancreatitis. Gastroenterology 1996;110:639–642. Heresbach D, Letourneur JP, Bahon I, Pagenault M, Guillou YM, Dyard F, Fauchet R, Malledant Y, Bretagne JF, Gosselin M. Value of early blood Th-1 cytokine determination in predicting severity of acute pancreatitis. Scand J Gastroenterol 1998;33:554–560. Curley P, Nestor M, Collins K, Saparoschetz I, Mendez M, Mannick J, Rodrick M. Decreased interleukin 2 production in murine acute pancreatitis: potential for immunomodulation. Gastroenterology 1996;110:583–588. Vallance BA, Hewlett B, Snider D, Collins S. T cell–mediated exocrine pancreatic damage in major histocompatibiliy complex class II–deficient mice. Gastroenterology 1998;115:978–987. Washington K, Gossage DL, Gottfried MR. Pathology of the pancreas in severe combined immunodeficiency and DiGeorge syndrome: acute graft-versus-host disease and unusual viral infections. Hum Pathol 1994;25:908–914.
EDITORIALS 629
28. Straumann A, Bauer M, Pichler WJ, Pirovino M. Acute pancreatitis due to pyritinol: an immune-related phenomenon. Gastroenterology 1998;115:452–454. 29. Jaray J, Perner F, Alfoldy F, Onody K. Mixed lymphocyte cultures (MLC) and acute pancreatitis after renal transplantation. Int Urol Nephrol 1981;13:391–394. 30. Ebert M, Ademmer K, Mu¨ller Ostermeyer F, Malfartheiner P. CD8⫹CD103⫹ T cells analogous to intestinal intraepithelial lymphocytes infiltrate the pancreas in chronic pancreatitis. Am J Gastroenterol 1999;93:2141–2147. 31. Mu¨ller Ostermeyer F, Ebert M, Malfartheiner P, Schubert W. T-cell receptor Valpha gene expression of infiltrating T cells in pancreatic cancer. Scand J Gastroenterol 1998;33:872–879. 32. Emmerich J, Weber H, Nausch M. Immunohistochemical characterization of the pancreatic cellular infiltrate in normal pancreas, chronic pancreatitis and pancreatic carcinoma. Digestion 1998; 59:192–198. 33. Hunger RE, Mueller C, Z’graggen K, Friess H, Buchler MW. Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology 1997;112:1656–1663.
Address requests for reprints to: Hans G. Beger, M.D., Department of General Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany. e-mail: [email protected]; fax: (49) 73-1-502-7209. r 2000 by the American Gastroenterological Association 0016-5085/00/$10.00
by TNB-induced colitis in rats. However, because none of the strategies used so far including the central blockade of the interleukin-1 receptor and the inhibition of prostaglandin or serotonin synthesis were able to restore normal feeding on the first days after TNB administration, simultaneous alterations of multiple pathways regulating food intake must come into play. This field of investigation would therefore benefit from recent advances made in the identification of several new hypothalamic neuropeptides and receptors that affect food intake and energy balance.16 Unraveling how these molecules, their neuronal systems, and receptors are modulated during colitis and their relationship to serotonin may provide additional insights to the circuitries between peripheral immune signals and the hypothalamic effector pathways in anorexia. YVETTE TACHE´ Digestive Diseases Division Digestive Diseases Research Center Department of Medicine, University of California Los Angeles, California
References 1. Gee MI, Grace MG, Wensel RH, Sherbaniuk R, Thomson AB. Protein-energy malnutrition in gastroenterology outpatients: increased risk in Crohn’s disease. J Am Diet Assoc 1985;85:1466– 1474. 2. Rigaud D, Angel LA, Cerf M, Carduner MJ, Melchior JC, Sautier C, Rene E, Apfelbaum M, Mignon M. Mechanisms of decreased food intake during weight loss in adult Crohn’s disease patients without obvious malabsorption. Am J Clin Nutr 1994;60:775– 781. 3. McCartney S, Ballinger A. Growth failure in inflammatory bowel disease (editorial). Nutrition 1999;15:169–171. 4. Ballinger A. Divergency of leptin response in intestinal inflammation. Gut 1999;44:588–589.
GASTROENTEROLOGY Vol. 118, No. 3
5. Kim HS, Berstad A. Experimental colitis in animal models. Scand J Gastroenterol 1992;27:529–537. 6. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 1995; 109:1344–1367. 7. McHugh KJ, Weingarten HP, Keenan C, Wallace JL, Collins SM. On the suppression of food intake in experimental models of colitis in the rat. Am J Physiol 1993;264:R871–R876. 8. Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 1989;96:795–803. 9. McHugh K, Castonguay TW, Collins SM, Weingarten HP. Characterization of suppression of food intake following acute colon inflammation in the rat. Am J Physiol 1993;265:R1001–R1005. 10. Larson SJ, Collins SM, Weingarten HP. Dissociation of temperature changes and anorexia after experimental colitis and LPS administration in rats. Am J Physiol 1996;271:R967–R972. 11. McHugh KJ, Collins SM, Weingarten HP. Central interleukin-1 receptors contribute to suppression of feeding after acute colitis in the rat. Am J Physiol 1994;266:R1659–R1663. 12. Barbier M, Cherbut C, Aube AC, Blottiere HM, Galmiche JP. Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 1998;43:783–790. 13. Leibowitz SF, Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 1998;44:851–864. 14. Ballinger A, El-Haj T, Perrett D, Turvill J, Obeid O, Dryden S, Williams G, Farthing MJG. The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis. Gastroenterology 2000;118:544–553. 15. Koprowska M, Krotewicz M, Romaniuk A, Strzelczuk M, Wieczorek M. Behavioral and neurochemical alterations evoked by p-chlorophenylalanine application in rats examined in the lightdark crossing test. Acta Neurobiol Exp (Warsz) 1999;59:15–22. 16. Lawrence CB, Turnbull AV, Rothwell NJ. Hypothalamic control of feeding. Curr Opin Neurobiol 1999;9:778–783. Address requests for reprints to: Yvette Tache ´, Ph.D., Department of Medicine, UCLA School of Medicine, 11301 Wilshire Boulevard, Los Angeles, California 90073-1792. e-mail: [email protected]; fax: (310) 268-4963. r 2000 by the American Gastroenterological Association 0016-5085/00/$10.00
The Role of Immunocytes in Acute and Chronic Pancreatitis: When Friends Turn Into Enemies See articles on pages 573 and 582.
he articles by Okazaki1 and Demols2 and their colleagues in this issue of GASTROENTEROLOGY assign immunocytes an important role in both acute and chronic pancreatitis. In acute pancreatitis, they act as the principal contributor to the acute systemic inflammatory response that determines early severity. In cases of autoimmune chronic pancreatitis, they are identified as
T
the cells responsible for perpetuating the chronic inflammatory process of the pancreatic gland. In acute pancreatitis, although late sepsis-related deaths resulting from infection of pancreatic necrosis can be countered by antibiotic treatment, some early deaths seem to be unavoidable because of serious multiorgan dysfunction.3 Moderating the overwhelming severe systemic inflammatory response has been found to prevent early complications and reduce severity in early acute pancreatitis.4 As a result, considerable effort has been put
March 2000
into developing treatments to do just this,5 as exemplified by anti–tumor necrosis factor ␣ antibody,6 interleukin (IL)-1 receptor antagonist,7 anti–intercellular adhesion molecule (ICAM),8 IL-10,9 or anti-CD3 antibodies.10 In view of its possible clinical impact, studying the role of immunocytes (e.g., granulocytes, macrophages, and lymphocytes) in pancreatitis is at present one of the most important topics in pancreatitis research. Devising new approaches to treat pancreatitis by influencing the complex immune response may soon further improve survival in this frequent and still dangerous disease.
Immunocytes in Acute Pancreatitis Polymorphonuclear (PMN)-granulocytes play a central role in the development of local, as well as systemic, complications of severe acute pancreatitis. Infiltrating PMNs, in part through production of oxygen free radicals, aggravate acute pancreatitis and contribute to local destruction and systemic complications.11 Recognition of the role of PMN-granulocytes has led to strategies to deplete PMN-granulocytes as therapeutic intervention in acute pancreatitis. Infiltrating neutrophils and macrophages are responsible for the intrapancreatic IL-1 production during acute pancreatitis, and their elimination by PMN antiserum significantly decreases the severity of pancreatic tissue destruction.12 Depletion of neutrophil granulocytes ameliorates the severity of acute pancreatitis in the early course of the disease and is associated with an increase in apoptotic cells in the later stage of experimental acute pancreatitis.13 Furthermore, pretreatment with antineutrophil serum completely prevents lung injury in acute pancreatitis14 and significantly reduced vacuolization in cerulein-induced pancreatitis in rats.13 There is also a large body of direct and indirect evidence for the involvement of lymphocytes in acute pancreatitis. If an overwhelming severe early systemic inflammatory response triggers pancreatic and systemic complications in acute pancreatitis, and immunocytes are responsible for these, anti-inflammatory therapy should reduce systemic complications. Indeed, a variety of agents including anti-ICAM antibodies,8 IL-10,9,15 the interleukin-1 receptor antagonist,16 anti-inflammatory peptides (e.g., CNI-149317), use of the recombinant plateletactivating factor acetyl hydrolase rPAF-AH,18 corticosteroids,19 anti-CD3 antibodies, and the calcineurin antagonist FK50610 have been found to reduce severity in early acute pancreatitis. Of interest, Russian groups used immunosuppressants
EDITORIALS 627
such as cyclophosphamide in the treatment of severe acute pancreatitis as early as the 1970s.20 Recently, our group has substantiated the pathophysiological basis of this treatment strategy by showing that the absence of active lymphocytes in mice with severe combined immunodeficiency disease is associated with reduced severity of acute pancreatitis.21 In acute pancreatitis, the number and ratio of CD4⫹ and CD8⫹ lymphocytes change dramatically, suggesting that T lymphocytes, primarily CD4⫹ T-helper (Th) cells may be involved in the events leading to severe pancreatitis.22 The IL-2 receptor is expressed mainly on activated lymphocytes, and in severe acute pancreatitis, the amount of soluble IL-2 receptor is increased in serum22 consistently. It has been suggested that an inadequate Th1 response in early acute pancreatitis is associated with systemic but not local complications.23 The determination of blood Th1 cytokines in early acute pancreatitis has been found to predict severity,24 and lymphocyteassociated cytokines may be suitable markers for monitoring acute pancreatitis.23 Conversely, attenuating IL-2– mediated Th1 activation, e.g., by a calcineurin inhibitor, typically reduces the severity of experimental acute pancreatitis.10 Paradoxically, an increased susceptibility to sepsis has been observed in a later stage of the disease, presumed to result from impaired immune function. Ironically, it could also be overcome by treatment with IL-2.25 Presumably, acute pancreatitis is, immunologically speaking, a two-phase disease: an initial hyperstimulation of the immune system, which causes early systemic complications, is followed by a variably long period of immune suppression, increasing the susceptibility for bacterial or fungal infection and, consequently, morbidity caused by sepsis. Other experimental and clinical observations lend further support to the inference that lymphocytes can play an important role in the pathophysiology of pancreatitis. Aged major histocompatibility complex (MHC) II–deficient mice ‘‘spontaneously’’ develop an immunebased pancreatitis with a selective loss of exocrine cells and functions, providing a model of immune-based pancreatic injury.26 Clinically, acute immune-related pancreatitis is a frequent finding in acute graft-versus-host disease in children with severe combined immunodeficiency and DiGeorge syndrome.27 The observation that the drug pyritinol may cause immune-related pancreatitis by activating CD4/CD8 lymphocytes28 is further indicative of the role lymphocytes play in acute pancreatitis, as is the suggested involvement of abnormal lymphocyte responsiveness in patients developing acute pancreatitis after renal transplantation.29
628 EDITORIALS
Immunocytes in Chronic Pancreatitis Some recent studies have focused on the role of nonspecific activation of PMN leukocytes locally, and immunocytes belonging to the T-cell family systemically, in chronic pancreatitis. Several groups have characterized the infiltrating lymphocytes present in tissue specimens of chronic pancreatitis.30–32 All investigators found an increased number of infiltrating lymphocytes, and most groups support the hypothesis of an involvement of cell-mediated cytotoxicity in the pathogenesis of chronic pancreatitis, as shown by elevated frequencies of perforin-expressing cells33 or CD8⫹CD103⫹ T cells30 in human chronic pancreatitis. In contrast to this hypothesis of cell-mediated toxicity, Emmerich et al.32 found a more acute inflammatory type of infiltrating lymphocytes in chronic pancreatitis tissue specimens. However, the chronic pancreatitis specimens investigated were not subdivided into idiopathic, alcoholic, or autoimmune chronic pancreatitis, making it impossible to specify and identify a special type of immune cell infiltration in the different types of chronic pancreatitis. The idea of an autoimmune action as the trigger for a subtype of chronic pancreatitis has been proposed for more than 30 years since Sarles first described pancreatitis associated with hypergammaglobulinemia. In the study by Okazaki et al.,1 the authors detected high autoantibodies against lactoferrin, carbonic anhydrase II, and other typical autoimmune targets in the sera of patients with autoimmune pancreatitis. In a detailed analysis of peripheral blood T cells from these patients, they found a Th1 type–mediated immune response, which is characterized by predominant cellular immunity, macrophage activation, cytotoxicity, and support of B-cell function including production of opsonizing and complement-fixing antibodies. These observations support the conclusion that this destructive form of chronic pancreatitis is mediated by autoimmune processes, and that this type of autoimmune pancreatitis clinically responds well to steroid therapy. In conclusion, several studies during the past decade have advanced our understanding of the role of immunocytes in acute and autoimmune chronic pancreatitis, systemically in the former and locally in the latter. The clinical implication of these observations, i.e., the potential utility of immunosuppressive therapy, offers new hope for more effective treatment of these diseases. HANS G. BEGER FRANK GANSAUGE JENS M. MAYER Department of General Surgery University of Ulm Ulm, Germany
GASTROENTEROLOGY Vol. 118, No. 3
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Address requests for reprints to: Hans G. Beger, M.D., Department of General Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany. e-mail: [email protected]; fax: (49) 73-1-502-7209. r 2000 by the American Gastroenterological Association 0016-5085/00/$10.00