- Email: [email protected]
Adhesion molecules in lymphocyte trafficking and colitis
1008
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EDITORIALS
Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18:2193–200. Ravnik-Glavac M, Potocnik U, Glavac D. Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 2000;37:533–536. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997;17:271–272. Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP. Germ-line msh6 mutations in colorectal cancer families. Cancer Res 1999;59:5068 –5074. Wijnen J, van der Klift H, Vasen H, Khan PM, Menko F, Tops C, Meijers Heijboer H, Lindhout D, Møller P, Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 1998;20:326 –328. Yan H, Papadopoulos N, Marra G, Perrera C, Jiricny J, Boland CR, Lynch HT, Chadwick RB, de la Chapelle A, Berg K, Eshelman JR, Yuan W, Markowitz S, Laken SJ, Lengauer C, Kinzler KW, Vogelstein B. Conversion of diploidy to haploidy. Nature 2000;403:723–724. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on HNPCC. Anticancer Res 1994;14:1661– 1664. Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Møller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998;339:511–518. Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 2000;37:641– 645.
GASTROENTEROLOGY Vol. 121, No. 4
22. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–1456. 23. Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch H, Perucho M, Smyrk T, Sobin L, Srivastava S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758 –1762. 24. Giardiello FM, Brensinger JD, Petersen GM, Luce MC, Hylind LM, Bacon JA, Booker SV, Parker RD, Hamilton SR. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997;336:823– 827. 25. Wijnen J, de Leeuw W, Vasen H, van der Klift H, Møller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Mo¨slein G, Tops C, Bro¨cker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 1999;23:142–144. 26. American Gastroenterological Association Medical Position Statement: Hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:195–197. 27. Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:198 –213.
Address requests for reprints to: Jonathan P. Terdiman, M.D., Box 1623, University of California, San Francisco, San Francisco, California 94143. e-mail: [email protected]; fax: (415) 502-2249. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.28634
Adhesion Molecules in Lymphocyte Trafficking and Colitis See articles on pages 853 and 958.
his issue contains 2 interesting, novel observations concerning the role of leukocyte and endothelial adhesion molecules in lymphocyte trafficking1 and in intestinal lesions.2 Both studies were conducted with human material, suggesting that some of the observations could be of direct clinical relevance. Lymphocyte trafficking to secondary lymphatic organs including peripheral lymph nodes, Peyer’s patches, bone marrow, spleen, and mesenteric lymph nodes is largely governed by adhesion molecules on lymphocytes, called homing receptors, and corresponding ligands on endothelial cells, called vascular addressins.3 Two key systems for lymphocyte homing are L-selectin on lymphocytes interacting with peripheral node addressin (PNAd), a mixture of glycoproteins expressed in high endothelial venules that supports L-selectin– dependent binding, and ␣47 integrin interacting with mucosal addressin cell adhesion molecule 1 (MAdCAM-1). In Salmi et al.’s report,1 careful and systematic investigation of
T
MAdCAM-1 expression in various tissues harvested from fetuses and children of various ages suggests developmental regulation of this important endothelial adhesion molecule and, by inference, this homing pathway. In adults, MAdCAM-1 directs homing of lymphocytes to the gut and gut-associated lymphatic tissues.4 The present study suggests that this restricted expression is acquired during embryonic development. This is supported by the fetal expression (7–17 weeks gestation) of MAdCAM-1 in the microvessels of many extraintestinal tissues, including peripheral lymph nodes, thymus, spleen, pancreas, skin, muscle, and kidney. This pattern of expression suggests that MAdCAM-1 may serve a much less gastrointestinal-specific role in lymphocyte homing in fetuses (and young children) than in adults. Concomitant analysis of ␣47 expression on cord blood lymphocytes showed an increased proportion of cells expressing both ␣47 integrins, the principal MAdCAM-1 ligand, and L-selectin, the ligand for PNAd. In adult blood lymphocytes, more cells express either ␣47 or L-selectin, although the majority still
October 2001
expresses both. These findings suggest that lymphocyte homing patterns continue to develop in utero and even in postnatal life. This study represents the first systematic description of MAdCAM-1 expression in human development. The function of the ␣47–MAdCAM-1 system seems to be much broader and more important in the fetal organism than in adults. Interestingly, the expression of MAdCAM-1 coincides with the development of lymphoid organs. Perhaps, this observation might open avenues for investigating developmental aspects of the immune response such as induction of tolerance and the “mucosaldominant” immune system in fetuses and young children. The other study2 describes a patient with a moderate form of leukocyte adhesion deficiency 1 (LAD-1) who develops chronic intestinal inflammation that resembles Crohn’s disease. LAD-1 is caused by sporadic mutations in the gene encoding the common CD18 chain of 2 integrins. Absence or reduction of 2 expression causes a concomitant loss of the corresponding ␣ chains, CD11a (␣L), CD11b (␣M), CD11c (␣x), and CD11d (␣d), because only the intact ␣ heterodimers can be expressed on the cell surface. LAD-1 patients typically present with skin ulcerations, gingivitis, and, in the severe form, die in infancy. Treatment options include bone marrow transplantation with CD18-competent bone marrow, which can be curative, because 2 integrins are only expressed on bone marrow– derived cells. LAD-1 is not uniformly associated with inflammatory bowel disease (IBD), but at least one report5 has shown that successful bone marrow transplantation can lead to reversal of gut inflammation. The present study2 shows plasma cell, lymphocyte, and eosinophil infiltration in the gut wall in proximity to ulcerative lesions, but almost no neutrophils. This histology is very distinct from both Crohn’s disease and ulcerative colitis. The absence of neutrophils is typical for lesions in CD18integrin– deficient human subjects,6 mice,7 and in profoundly neutropenic humans with colitis.8,9 The authors conclude from their observation of intestinal lesions in an LAD-1 patient that inhibiting LFA-1 (␣L2 integrin) or its ligand, intercellular adhesion molecule 1 (ICAM-1), for therapeutic purposes in IBD may not be beneficial. The authors suggest that adhesion molecule deficiency, in this case, was not “protective.” However, a potential “protective” role of blocking or eliminating adhesion molecules was not tested in this study. Indeed, absence or deficiency of proinflammatory adhesion molecules in humans6,10 and mice7,11,12 often leads to inflammatory disease. Similarly, the association of chronic inflammation in the distal intestine in children with chronic granulomatous disease, a defect in bacterial killing by neutrophils, has led Korzenik et al.13
EDITORIALS
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to postulate that chronic disease is a consequence of neutrophil dysfunction. This theory is supported by a pilot study reporting therapeutic responses to granulocyte colony–stimulating factor (G-CSF) in patients with refractory Crohn’s disease.14 These observations seem paradoxical at first, but become understandable when considering the unbalanced proinflammatory effect of defective host responses to pathogens or translocating resident enteric bacteria after a breach in the mucosal barrier induced by noxious stimuli. Eliminating leukocyte or endothelial adhesion molecules leads to increased neutrophil production, possibly via a neutrophilia-inducing effect of subclinical infections15 or via an endogenous feedback loop that involves G-CSF and interleukin 17.16 Treatment regimens aimed at curbing exuberant inflammation by blocking adhesion molecules, for example, in models of IBD,17 are designed to block leukocyte or endothelial adhesion molecules for a limited time, for example, 3 days, to break the cycle of inflammation without upsetting internal regulatory systems and without compromising host defense. Indeed, Uzel et al.2 found bacteria on the surface of the intestinal lesions, suggesting that this LAD-1 patient was unable to effectively and expediently clear pathogens or invading commensal bacteria because of a neutrophil trafficking defect secondary to reduced expression of 2 integrins. The advent of experimental therapeutics aimed at leukocyte and endothelial adhesion molecules, including MAdCAM-1 and ␣47,18 –20 2 integrins21 and ICAM1,22 and their experimental use in patients with IBD, has raised the interest in targeting adhesion molecules for therapeutic purposes. Major challenges remain. Adhesion molecule blockers are of relatively low affinity and use large numbers of receptors on either cell (Velcro-type interaction). The development of potent, specific, and long-lived small molecule inhibitors of adhesion molecules has remained difficult. Studies using antisense strategies22 or antibodies23–25 have mechanistic limitations because of the biological nature of experimental therapeutics. The 2 papers in this issue contribute to our understanding of the expression pattern and function of leukocyte-endothelial adhesion molecules and thus help in laying the groundwork for future therapeutic and diagnostic applications. KLAUS LEY Cardiovascular Research Center and Department of Biomedical Engineering University of Virginia CARTLAND BURNS Department of Surgery University of Virginia Charlottesville, Virginia
1010
EDITORIALS
GASTROENTEROLOGY Vol. 121, No. 4
References 1. Salmi M, Alanen K, Renman S, Briskin M, Butcher EC, Jalkanen S. Immune cell trafficking in utero and during early life is dominated by the mucosal addressin MAdCAM-1 in man. Gastroenterology 2001;121:853– 864. 2. Uzel G, Kleiner DE, Kuhns DB, Holland SM. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology 2001;121:958 –964. 3. Picker LJ, Butcher EC. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol 1992;10:561–591. 4. Briskin M, Winsorhines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, MacKay CR, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997;151:97–110. 5. D’Agata ID, Paradis K, Chad Z, Bonny Y, Seidman E. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut 1996; 39:605– 608. 6. Harlan JM. Leukocyte adhesion deficiency syndrome: insights into the molecular basis of leukocyte emigration. Clin Immunol 1993;67:S16 –24. 7. Scharffetter-Kochanek K, Lu HF, Norman K, Vannood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med 1998;188:119 –131. 8. Sadulla S, Nagesh K, Johnston D, McCullough JB, Burray F, Cachia PG. Recurrent septicaemia in a neutropenic patient with typhlitis. Clin Lab Haematol 1996;18:215–217. 9. Boggio L, Pooley R, Roth SI, Winter JN. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transplant 2000;25:321–326. 10. Becker DJ, Lowe JB. Leukocyte adhesion deficiency type II. Biochim Biophys Acta 1999;1455:193–204. 11. Bullard DC, Kunkel EJ, Kubo H, Hicks MJ, Lorenzo I, Doyle NA, Doerschuk CM, Ley K, Beaudet AL. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J Exp Med 1996;183: 2329 –2336. 12. Forlow SB, White EJ, Barlow SC, Feldman SH, Lu H, Bagby GJ, Beaudet AL, Bullard DC, Ley K. Severe inflammatory defect and reduced viability in CD18 and E-selectin double mutant mice. J Clin Invest 2000;106:1457–1466. 13. Korzenik JR, Dieckgraefe BK. Is Crohn’s disease an immunodeficiency? A hypothesis suggesting early events in the pathogenesis of Crohn’s disease. Dig Dis Sci 2000;45:1121–1129. 14. Korzenik JR, Dieckgraefe BJ. Immunostimulation in Crohn’s disease: results of a pilot study of G-CSF in mucosal and fistulizing Crohn’s disease (abstr). Gastroenterology 2000;118:A874 – 875. 15. Horwitz BH, Mizgerd JP, Scott ML, Doerschuk CM. Mechanisms
16.
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of granulocytosis in the absence of CD18. Blood 2001;97: 1578 –1583. Forlow SB, Schurr JR, Kolls JK, Bagby GJ, Schwarzenberger PS, Ley K. Increased granulopoiesis through IL-17 and G-CSF in adhesion molecule-deficient mice. Blood 2001;in press. Burns RC, Rivera-Nieves J, Moskaluk CA, Matsumoto S, Cominelli F, Ley K. Antibody blockade of ICAM-1 and VCAM-1 ameliorates inflammation in the SAMP-1/Yit adoptive transfer model of Crohn’s disease. Gastroenterology 2001;in press. Kanwar JR, Kanwar RK, Wang D, Krissansen GW. Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression. Immunol Cell Biol 2000;78:641– 645. Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E, Ringler DJ. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4⫹ T cells. J Immunol 1997;158:2099 –2106. Palecanda A, Marshall JS, Li X, Briskin MJ, Issekutz TB. Selective antibody blockade of lymphocyte migration to mucosal sites and mast cell adhesion. J Leukoc Biol 1999;65:649 – 657. Meenan J, Hommes DW, Mevissen M, Dijkhuizen S, Soule H, Moyle M, Buller HR, ten Kate FW, Tytgat GN, van Deventer SJ. Attenuation of the inflammatory response in an animal colitis model by neutrophil inhibitory factor, a novel beta 2-integrin antagonist. Scand J Gastroenterol 1996;31:786 –791. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, Shanahan WR Jr. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn’s disease. Gastroenterology 1998;114:1133–1142. Lockwood CM, Elliott JD, Brettman L, Hale G, Rebello P, Frewin M, Ringler D, Merrill C, Waldmann H. Anti-adhesion molecule therapy as an interventional strategy for autoimmune inflammation. Clin Immunol 1999;93:93–106. Lin KC, Castro AC. Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents. Curr Opin Chem Biol 1998;2: 453– 457. Curley GP, Blum H, Humphries MJ. Integrin antagonists. Cell Mol Life Sci 1999;56:427– 441.
Address requests for reprints to: Klaus Ley, M.D., Ph.D., Department of Biomedical Engineering, University of Virginia Health System, P.O. Box 800759, Charlottesville, Virginia 22908-0759. e-mail: [email protected]; fax: (434) 982-3870. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.28635
The Role of Glutathione S-Transferase P1-1 in Colorectal Cancer: Friend or Foe? See article on page 865.
lutathione S-transferase P1-1 (GSTP1-1) is a member of the glutathione S-transferase enzyme superfamily.1 In humans, the GST superfamily includes enzymes of the ␣, , , , , and microsomal classes. These
G
enzymes can be found in bacteria and plants as well as in animals. With the exception of the microsomal class, these enzymes are principally found in the cytosol of mammalian cells. These enzymes catalyze the reaction of electrophilic organic compounds with the nucleophilic sulfhydryl group of glutathione to form a variety of conjugates that are often further converted to mercaptu-
14.
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18.
19.
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EDITORIALS
Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18:2193–200. Ravnik-Glavac M, Potocnik U, Glavac D. Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 2000;37:533–536. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997;17:271–272. Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP. Germ-line msh6 mutations in colorectal cancer families. Cancer Res 1999;59:5068 –5074. Wijnen J, van der Klift H, Vasen H, Khan PM, Menko F, Tops C, Meijers Heijboer H, Lindhout D, Møller P, Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 1998;20:326 –328. Yan H, Papadopoulos N, Marra G, Perrera C, Jiricny J, Boland CR, Lynch HT, Chadwick RB, de la Chapelle A, Berg K, Eshelman JR, Yuan W, Markowitz S, Laken SJ, Lengauer C, Kinzler KW, Vogelstein B. Conversion of diploidy to haploidy. Nature 2000;403:723–724. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on HNPCC. Anticancer Res 1994;14:1661– 1664. Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Møller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998;339:511–518. Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 2000;37:641– 645.
GASTROENTEROLOGY Vol. 121, No. 4
22. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–1456. 23. Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch H, Perucho M, Smyrk T, Sobin L, Srivastava S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758 –1762. 24. Giardiello FM, Brensinger JD, Petersen GM, Luce MC, Hylind LM, Bacon JA, Booker SV, Parker RD, Hamilton SR. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997;336:823– 827. 25. Wijnen J, de Leeuw W, Vasen H, van der Klift H, Møller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Mo¨slein G, Tops C, Bro¨cker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 1999;23:142–144. 26. American Gastroenterological Association Medical Position Statement: Hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:195–197. 27. Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:198 –213.
Address requests for reprints to: Jonathan P. Terdiman, M.D., Box 1623, University of California, San Francisco, San Francisco, California 94143. e-mail: [email protected]; fax: (415) 502-2249. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.28634
Adhesion Molecules in Lymphocyte Trafficking and Colitis See articles on pages 853 and 958.
his issue contains 2 interesting, novel observations concerning the role of leukocyte and endothelial adhesion molecules in lymphocyte trafficking1 and in intestinal lesions.2 Both studies were conducted with human material, suggesting that some of the observations could be of direct clinical relevance. Lymphocyte trafficking to secondary lymphatic organs including peripheral lymph nodes, Peyer’s patches, bone marrow, spleen, and mesenteric lymph nodes is largely governed by adhesion molecules on lymphocytes, called homing receptors, and corresponding ligands on endothelial cells, called vascular addressins.3 Two key systems for lymphocyte homing are L-selectin on lymphocytes interacting with peripheral node addressin (PNAd), a mixture of glycoproteins expressed in high endothelial venules that supports L-selectin– dependent binding, and ␣47 integrin interacting with mucosal addressin cell adhesion molecule 1 (MAdCAM-1). In Salmi et al.’s report,1 careful and systematic investigation of
T
MAdCAM-1 expression in various tissues harvested from fetuses and children of various ages suggests developmental regulation of this important endothelial adhesion molecule and, by inference, this homing pathway. In adults, MAdCAM-1 directs homing of lymphocytes to the gut and gut-associated lymphatic tissues.4 The present study suggests that this restricted expression is acquired during embryonic development. This is supported by the fetal expression (7–17 weeks gestation) of MAdCAM-1 in the microvessels of many extraintestinal tissues, including peripheral lymph nodes, thymus, spleen, pancreas, skin, muscle, and kidney. This pattern of expression suggests that MAdCAM-1 may serve a much less gastrointestinal-specific role in lymphocyte homing in fetuses (and young children) than in adults. Concomitant analysis of ␣47 expression on cord blood lymphocytes showed an increased proportion of cells expressing both ␣47 integrins, the principal MAdCAM-1 ligand, and L-selectin, the ligand for PNAd. In adult blood lymphocytes, more cells express either ␣47 or L-selectin, although the majority still
October 2001
expresses both. These findings suggest that lymphocyte homing patterns continue to develop in utero and even in postnatal life. This study represents the first systematic description of MAdCAM-1 expression in human development. The function of the ␣47–MAdCAM-1 system seems to be much broader and more important in the fetal organism than in adults. Interestingly, the expression of MAdCAM-1 coincides with the development of lymphoid organs. Perhaps, this observation might open avenues for investigating developmental aspects of the immune response such as induction of tolerance and the “mucosaldominant” immune system in fetuses and young children. The other study2 describes a patient with a moderate form of leukocyte adhesion deficiency 1 (LAD-1) who develops chronic intestinal inflammation that resembles Crohn’s disease. LAD-1 is caused by sporadic mutations in the gene encoding the common CD18 chain of 2 integrins. Absence or reduction of 2 expression causes a concomitant loss of the corresponding ␣ chains, CD11a (␣L), CD11b (␣M), CD11c (␣x), and CD11d (␣d), because only the intact ␣ heterodimers can be expressed on the cell surface. LAD-1 patients typically present with skin ulcerations, gingivitis, and, in the severe form, die in infancy. Treatment options include bone marrow transplantation with CD18-competent bone marrow, which can be curative, because 2 integrins are only expressed on bone marrow– derived cells. LAD-1 is not uniformly associated with inflammatory bowel disease (IBD), but at least one report5 has shown that successful bone marrow transplantation can lead to reversal of gut inflammation. The present study2 shows plasma cell, lymphocyte, and eosinophil infiltration in the gut wall in proximity to ulcerative lesions, but almost no neutrophils. This histology is very distinct from both Crohn’s disease and ulcerative colitis. The absence of neutrophils is typical for lesions in CD18integrin– deficient human subjects,6 mice,7 and in profoundly neutropenic humans with colitis.8,9 The authors conclude from their observation of intestinal lesions in an LAD-1 patient that inhibiting LFA-1 (␣L2 integrin) or its ligand, intercellular adhesion molecule 1 (ICAM-1), for therapeutic purposes in IBD may not be beneficial. The authors suggest that adhesion molecule deficiency, in this case, was not “protective.” However, a potential “protective” role of blocking or eliminating adhesion molecules was not tested in this study. Indeed, absence or deficiency of proinflammatory adhesion molecules in humans6,10 and mice7,11,12 often leads to inflammatory disease. Similarly, the association of chronic inflammation in the distal intestine in children with chronic granulomatous disease, a defect in bacterial killing by neutrophils, has led Korzenik et al.13
EDITORIALS
1009
to postulate that chronic disease is a consequence of neutrophil dysfunction. This theory is supported by a pilot study reporting therapeutic responses to granulocyte colony–stimulating factor (G-CSF) in patients with refractory Crohn’s disease.14 These observations seem paradoxical at first, but become understandable when considering the unbalanced proinflammatory effect of defective host responses to pathogens or translocating resident enteric bacteria after a breach in the mucosal barrier induced by noxious stimuli. Eliminating leukocyte or endothelial adhesion molecules leads to increased neutrophil production, possibly via a neutrophilia-inducing effect of subclinical infections15 or via an endogenous feedback loop that involves G-CSF and interleukin 17.16 Treatment regimens aimed at curbing exuberant inflammation by blocking adhesion molecules, for example, in models of IBD,17 are designed to block leukocyte or endothelial adhesion molecules for a limited time, for example, 3 days, to break the cycle of inflammation without upsetting internal regulatory systems and without compromising host defense. Indeed, Uzel et al.2 found bacteria on the surface of the intestinal lesions, suggesting that this LAD-1 patient was unable to effectively and expediently clear pathogens or invading commensal bacteria because of a neutrophil trafficking defect secondary to reduced expression of 2 integrins. The advent of experimental therapeutics aimed at leukocyte and endothelial adhesion molecules, including MAdCAM-1 and ␣47,18 –20 2 integrins21 and ICAM1,22 and their experimental use in patients with IBD, has raised the interest in targeting adhesion molecules for therapeutic purposes. Major challenges remain. Adhesion molecule blockers are of relatively low affinity and use large numbers of receptors on either cell (Velcro-type interaction). The development of potent, specific, and long-lived small molecule inhibitors of adhesion molecules has remained difficult. Studies using antisense strategies22 or antibodies23–25 have mechanistic limitations because of the biological nature of experimental therapeutics. The 2 papers in this issue contribute to our understanding of the expression pattern and function of leukocyte-endothelial adhesion molecules and thus help in laying the groundwork for future therapeutic and diagnostic applications. KLAUS LEY Cardiovascular Research Center and Department of Biomedical Engineering University of Virginia CARTLAND BURNS Department of Surgery University of Virginia Charlottesville, Virginia
1010
EDITORIALS
GASTROENTEROLOGY Vol. 121, No. 4
References 1. Salmi M, Alanen K, Renman S, Briskin M, Butcher EC, Jalkanen S. Immune cell trafficking in utero and during early life is dominated by the mucosal addressin MAdCAM-1 in man. Gastroenterology 2001;121:853– 864. 2. Uzel G, Kleiner DE, Kuhns DB, Holland SM. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology 2001;121:958 –964. 3. Picker LJ, Butcher EC. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol 1992;10:561–591. 4. Briskin M, Winsorhines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, MacKay CR, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997;151:97–110. 5. D’Agata ID, Paradis K, Chad Z, Bonny Y, Seidman E. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut 1996; 39:605– 608. 6. Harlan JM. Leukocyte adhesion deficiency syndrome: insights into the molecular basis of leukocyte emigration. Clin Immunol 1993;67:S16 –24. 7. Scharffetter-Kochanek K, Lu HF, Norman K, Vannood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med 1998;188:119 –131. 8. Sadulla S, Nagesh K, Johnston D, McCullough JB, Burray F, Cachia PG. Recurrent septicaemia in a neutropenic patient with typhlitis. Clin Lab Haematol 1996;18:215–217. 9. Boggio L, Pooley R, Roth SI, Winter JN. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transplant 2000;25:321–326. 10. Becker DJ, Lowe JB. Leukocyte adhesion deficiency type II. Biochim Biophys Acta 1999;1455:193–204. 11. Bullard DC, Kunkel EJ, Kubo H, Hicks MJ, Lorenzo I, Doyle NA, Doerschuk CM, Ley K, Beaudet AL. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J Exp Med 1996;183: 2329 –2336. 12. Forlow SB, White EJ, Barlow SC, Feldman SH, Lu H, Bagby GJ, Beaudet AL, Bullard DC, Ley K. Severe inflammatory defect and reduced viability in CD18 and E-selectin double mutant mice. J Clin Invest 2000;106:1457–1466. 13. Korzenik JR, Dieckgraefe BK. Is Crohn’s disease an immunodeficiency? A hypothesis suggesting early events in the pathogenesis of Crohn’s disease. Dig Dis Sci 2000;45:1121–1129. 14. Korzenik JR, Dieckgraefe BJ. Immunostimulation in Crohn’s disease: results of a pilot study of G-CSF in mucosal and fistulizing Crohn’s disease (abstr). Gastroenterology 2000;118:A874 – 875. 15. Horwitz BH, Mizgerd JP, Scott ML, Doerschuk CM. Mechanisms
16.
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22.
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Address requests for reprints to: Klaus Ley, M.D., Ph.D., Department of Biomedical Engineering, University of Virginia Health System, P.O. Box 800759, Charlottesville, Virginia 22908-0759. e-mail: [email protected]; fax: (434) 982-3870. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.28635
The Role of Glutathione S-Transferase P1-1 in Colorectal Cancer: Friend or Foe? See article on page 865.
lutathione S-transferase P1-1 (GSTP1-1) is a member of the glutathione S-transferase enzyme superfamily.1 In humans, the GST superfamily includes enzymes of the ␣, , , , , and microsomal classes. These
G
enzymes can be found in bacteria and plants as well as in animals. With the exception of the microsomal class, these enzymes are principally found in the cytosol of mammalian cells. These enzymes catalyze the reaction of electrophilic organic compounds with the nucleophilic sulfhydryl group of glutathione to form a variety of conjugates that are often further converted to mercaptu-