[Frontiers In Bioscience, Landmark, 23, 1754-1779, June 1, 2018]

A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target

Kei Ohnuma1, Ryo Hatano1, Eriko Komiya1, Haruna Otsuka1, Takumi Itoh1, Noriaki Iwao2, Yutaro Kaneko3, Taketo Yamada4,5, Nam H. Dang6, Chikao Morimoto1

1Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan, 2Department of Hematology, Juntendo University Shizuoka Hospital, Nagaoka 1129, Izunokuni-city, Shizuoka 410-2295, Japan, 3Y’s AC Co., Ltd., 5-3-14, Toranomon, Minato-ku, Tokyo 105-0001, Japan, 4Department of Pathology, Keio University school of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, 5Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0459, Japan, 6Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road-Box 100278, Room MSB M410A, Gainesville, FL 32610, U.S.A.

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Immune mediated disorders
3.1. Chronic graft-versus-host disease
3.2. Middle East respiratory syndrome coronavirus
3.3. Psoriatic pruritus
4. Cancers
4.1. Novel mechanism of CD26/DPPIV in cancer immunology
4.2. Malignant pleural mesothelioma
4.3. Other cancers
5. Summary and perspectives
6. Acknowledgement
7. References

1. ABSTRACT

CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV activity that is expressed on numerous cell types and has a multitude of biological functions. The role of CD26 in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell-T-cell interaction. In this paper, we will review emerging data on CD26-mediated immune regulation suggesting that CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders as well as Middle East respiratory syndrome coronavirus. Moreover, we have had a long-standing interest in the role of CD26 in cancer biology and its suitability as a novel therapeutic target in selected neoplasms. We reported robust in vivo data on the anti-tumor activity of anti-CD26 monoclonal antibody in mouse xenograft models. We herein review significant novel findings and the early clinical development of a CD26-targeted therapy in selected immune disorders and cancers, advances that can lead to a more hopeful future for patients with these intractable diseases.

7. REFERENCES

1. D. A. Fox, R. E. Hussey, K. A. Fitzgerald, O. Acuto, C. Poole, L. Palley, J. F. Daley, S. F. Schlossman and E. L. Reinherz: Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody. J Immunol, 133(3), 1250-6 (1984)

2. D. M. Nanus, D. Engelstein, G. A. Gastl, L. Gluck, M. J. Vidal, M. Morrison, C. L. Finstad, N. H. Bander and A. P. Albino: Molecular cloning of the human kidney differentiation antigen gp160: human aminopeptidase A. Proc Natl Acad Sci U S A, 90(15), 7069-73 (1993)
DOI: 10.1073/pnas.90.15.7069
PMid:8346219 PMCid:PMC47077

3. T. Tanaka, D. Camerini, B. Seed, Y. Torimoto, N. H. Dang, J. Kameoka, H. N. Dahlberg, S. F. Schlossman and C. Morimoto: Cloning and functional expression of the T cell activation antigen CD26. J Immunol, 149(2), 481-6 (1992)

4. I. De Meester, S. Korom, J. Van Damme and S. Scharpe: CD26, let it cut or cut it down. Immunol Today, 20(8), 367-75 (1999)
DOI: 10.1016/S0167-5699(99)01486-3

5. B. Fleischer: CD26: a surface protease involved in T-cell activation. Immunol Today, 15(4), 180-4 (1994)
DOI: 10.1016/0167-5699(94)90316-6

6. C. Morimoto and S. F. Schlossman: The structure and function of CD26 in the T-cell immune response. Immunol Rev, 161, 55-70 (1998)
DOI: 10.1111/j.1600-065X.1998.tb01571.x
PMid:9553764

7. A. von Bonin, J. Huhn and B. Fleischer: Dipeptidyl-peptidase IV/CD26 on T cells: analysis of an alternative T-cell activation pathway. Immunol Rev, 161, 43-53 (1998)
DOI: 10.1111/j.1600-065X.1998.tb01570.x
PMid:9553763

8. M. A. Thompson, K. Ohnuma, M. Abe, C. Morimoto and N. H. Dang: CD26/dipeptidyl peptidase IV as a novel therapeutic target for cancer and immune disorders. Mini Rev Med Chem, 7(3), 253-73 (2007)
DOI: 10.2174/138955707780059853
PMid:17346218

9. K. Ohnuma, N. H. Dang and C. Morimoto: Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol, 29(6), 295-301 (2008)
DOI: 10.1016/j.it.2008.02.010
PMid:18456553

10. P. A. Havre, M. Abe, Y. Urasaki, K. Ohnuma, C. Morimoto and N. H. Dang: The role of CD26/dipeptidyl peptidase IV in cancer. Front Biosci, 13, 1634-45 (2008)
DOI: 10.2741/2787
PMid:17981655

11. P. Busek, J. Stremenova and A. Sedo: Dipeptidyl peptidase-IV enzymatic activity bearing molecules in human brain tumors--good or evil? Front Biosci, 13, 2319-26 (2008)

12. L. Sromova, P. Busek, L. Sedova and A. Sedo: Intraindividual changes of dipeptidyl peptidase-IV in peripheral blood of patients with rheumatoid arthritis are associated with the disease activity. BMC Musculoskelet Disord, 16, 244 (2015)

13. K. Ohnuma, N. Takahashi, T. Yamochi, O. Hosono, N. H. Dang and C. Morimoto: Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci, 13, 2299-310 (2008)
DOI: 10.2741/2844
PMid:17981712

14. B. R. Blazar, W. J. Murphy and M. Abedi: Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol, 12(6), 443-58 (2012)
DOI: 10.1038/nri3212
PMid:22576252 PMCid:PMC3552454

15. H. J. Deeg, D. Lin, W. Leisenring, M. Boeckh, C. Anasetti, F. R. Appelbaum, T. R. Chauncey, K. Doney, M. Flowers, P. Martin, R. Nash, G. Schoch, K. M. Sullivan, R. P. Witherspoon and R. Storb: Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial. Blood, 89(10), 3880-7 (1997)

16. A. H. Filipovich: Diagnosis and manifestations of chronic graft-versus-host disease. Best Pract Res Clin Haematol, 21(2), 251-7 (2008)
DOI: 10.1016/j.beha.2008.02.008
PMid:18503990

17. G. Socie and J. Ritz: Current issues in chronic graft-versus-host disease. Blood, 124(3), 374-84 (2014)
DOI: 10.1182/blood-2014-01-514752
PMid:24914139 PMCid:PMC4102710

18. J. W. Chien, S. Duncan, K. M. Williams and S. Z. Pavletic: Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant, 16(1 Suppl), S106-14 (2010)

19. A. Z. Dudek, H. Mahaseth, T. E. DeFor and D. J. Weisdorf: Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant, 9(10), 657-66 (2003)
DOI: 10.1016/S1083-8791(03)00242-8

20. C. Nakaseko, S. Ozawa, E. Sakaida, M. Sakai, Y. Kanda, K. Oshima, M. Kurokawa, S. Takahashi, J. Ooi, T. Shimizu, A. Yokota, F. Yoshiba, K. Fujimaki, H. Kanamori, R. Sakai, T. Saitoh, T. Sakura, A. Maruta, H. Sakamaki and S. Okamoto: Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation. Int J Hematol, 93(3), 375-82 (2011)
DOI: 10.1007/s12185-011-0809-8
PMid:21424350

21. R. Zeiser and B. R. Blazar: Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood, 127(25), 3117-26 (2016)

22. R. Champlin, I. Khouri and S. Giralt: Graft-vs.-malignancy with allogeneic blood stem cell transplantation: a potential primary treatment modality. Pediatr Transplant, 3 Suppl 1, 52-8 (1999)
DOI: 10.1034/j.1399-3046.1999.00054.x

23. C. E. Rudd: T-cell signaling and immunopathologies. Semin Immunopathol, 32(2), 91-4 (2010)
DOI: 10.1007/s00281-010-0203-2
PMid:20238116

24. K. A. Markey, K. P. MacDonald and G. R. Hill: The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood, 124(3), 354-62 (2014)
DOI: 10.1182/blood-2014-02-514745
PMid:24914137 PMCid:PMC4102708

25. N. H. Dang, Y. Torimoto, K. Deusch, S. F. Schlossman and C. Morimoto: Comitogenic effect of solid-phase immobilized anti-1F7 on human CD4 T cell activation via CD3 and CD2 pathways. J Immunol, 144(11), 4092-100 (1990)

26. C. Morimoto, Y. Torimoto, G. Levinson, C. E. Rudd, M. Schrieber, N. H. Dang, N. L. Letvin and S. F. Schlossman: 1F7, a novel cell surface molecule, involved in helper function of CD4 cells. J Immunol, 143(11), 3430-9 (1989)

27. K. Ohnuma, T. Yamochi, M. Uchiyama, K. Nishibashi, N. Yoshikawa, N. Shimizu, S. Iwata, H. Tanaka, N. H. Dang and C. Morimoto: CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Proc Natl Acad Sci U S A, 101(39), 14186-91 (2004)
DOI: 10.1073/pnas.0405266101
PMid:15353589 PMCid:PMC521134

28. K. Ohnuma, T. Yamochi, M. Uchiyama, K. Nishibashi, S. Iwata, O. Hosono, H. Kawasaki, H. Tanaka, N. H. Dang and C. Morimoto: CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells. Mol Cell Biol, 25(17), 7743-57 (2005)
DOI: 10.1128/MCB.25.17.7743-7757.2005
PMid:16107720 PMCid:PMC1190283

29. K. Ohnuma, M. Uchiyama, T. Yamochi, K. Nishibashi, O. Hosono, N. Takahashi, S. Kina, H. Tanaka, X. Lin, N. H. Dang and C. Morimoto: Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J Biol Chem, 282(13), 10117-31 (2007)
DOI: 10.1074/jbc.M609157200
PMid:17287217

30. K. Ohnuma, M. Uchiyama, R. Hatano, W. Takasawa, Y. Endo, N. H. Dang and C. Morimoto: Blockade of CD26-mediated T cell costimulation with soluble caveolin-1-Ig fusion protein induces anergy in CD4+T cells. Biochem Biophys Res Commun, 386(2), 327-32 (2009)
DOI: 10.1016/j.bbrc.2009.06.027
PMid:19523449

31. B. Bengsch, B. Seigel, T. Flecken, J. Wolanski, H. E. Blum and R. Thimme: Human Th17 cells express high levels of enzymatically active dipeptidylpeptidase IV (CD26). J Immunol, 188(11), 5438-47 (2012)
DOI: 10.4049/jimmunol.1103801
PMid:22539793

32. R. Hatano, K. Ohnuma, J. Yamamoto, N. H. Dang, T. Yamada and C. Morimoto: Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody. Br J Haematol, 162(2), 263-77 (2013)
DOI: 10.1111/bjh.12378
PMid:23692598

33. K. Sato, H. Nagayama and T. A. Takahashi: Aberrant CD3- and CD28-mediated signaling events in cord blood T cells are associated with dysfunctional regulation of Fas ligand-mediated cytotoxicity. J Immunol, 162(8), 4464-71 (1999)

34. S. Kobayashi, K. Ohnuma, M. Uchiyama, K. Iino, S. Iwata, N. H. Dang and C. Morimoto: Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation. Blood, 103(3), 1002-10 (2004)
DOI: 10.1182/blood-2003-08-2691
PMid:14525771

35. L. D. Shultz, M. A. Brehm, J. V. Garcia-Martinez and D. L. Greiner: Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol, 12(11), 786-98 (2012)
DOI: 10.1038/nri3311
PMid:23059428 PMCid:PMC3749872

36. K. Tezuka, R. Xun, M. Tei, T. Ueno, M. Tanaka, N. Takenouchi and J. Fujisawa: An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity. Blood, 123(3), 346-55 (2014)
DOI: 10.1182/blood-2013-06-508861
PMid:24196073

37. K. Ohnuma, R. Hatano, T. M. Aune, H. Otsuka, S. Iwata, N. H. Dang, T. Yamada and C. Morimoto: Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes. J Immunol, 194(8), 3697-712 (2015)
DOI: 10.4049/jimmunol.1402785
PMid:25786689 PMCid:PMC4568737

38. P. L. Collins, M. A. Henderson and T. M. Aune: Lineage-specific adjacent IFNG and IL26 genes share a common distal enhancer element. Genes Immun, 13(6), 481-8 (2012)
DOI: 10.1038/gene.2012.22
PMid:22622197 PMCid:PMC4180225

39. R. P. Donnelly, F. Sheikh, H. Dickensheets, R. Savan, H. A. Young and M. R. Walter: Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor Rev, 21(5), 393-401 (2010)
DOI: 10.1016/j.cytogfr.2010.09.001
PMid:20947410 PMCid:PMC2997847

40. P. L. Collins, S. Chang, M. Henderson, M. Soutto, G. M. Davis, A. G. McLoed, M. J. Townsend, L. H. Glimcher, D. P. Mortlock and T. M. Aune: Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol, 185(3), 1492-501 (2010)
DOI: 10.4049/jimmunol.1000124
PMid:20574006 PMCid:PMC2923829

41. J. A. Engelman, X. Zhang, F. Galbiati, D. Volonte, F. Sotgia, R. G. Pestell, C. Minetti, P. E. Scherer, T. Okamoto and M. P. Lisanti: Molecular genetics of the caveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy. Am J Hum Genet, 63(6), 1578-87 (1998)
DOI: 10.1086/302172
PMid:9837809 PMCid:PMC1377628

42. C. J. Wu and J. Ritz: Revealing tumor immunity after hematopoietic stem cell transplantation. Clin Cancer Res, 15(14), 4515-7 (2009)
DOI: 10.1158/1078-0432.CCR-09-0873
PMid:19584145

43. D. Marguet, A. M. Bernard, I. Vivier, D. Darmoul, P. Naquet and M. Pierres: cDNA cloning for mouse thymocyte-activating molecule. A multifunctional ecto-dipeptidyl peptidase IV (CD26) included in a subgroup of serine proteases. J Biol Chem, 267(4), 2200-8 (1992)

44. S. Yan, D. Marguet, J. Dobers, W. Reutter and H. Fan: Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol, 33(6), 1519-27 (2003)
DOI: 10.1002/eji.200323469
PMid:12778469

45. A. M. Zaki, S. van Boheemen, T. M. Bestebroer, A. D. Osterhaus and R. A. Fouchier: Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med, 367(19), 1814-20 (2012)
DOI: 10.1056/NEJMoa1211721
PMid:23075143

46. WHO Programmes and Projects. Emergencies: Middle East resipratory syndrome cornavirus (MERS-CoV). http://www.who.int/emergencies/mers-cov/en/ (2017)

47. Y. Mo and D. Fisher: A review of treatment modalities for Middle East Respiratory Syndrome. J Antimicrob Chemother, 71(12), 3340-3350 (2016)
DOI: 10.1093/jac/dkw338
PMid:27585965

48. A. Zumla, J. F. Chan, E. I. Azhar, D. S. Hui and K. Y. Yuen: Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov, 15(5), 327-47 (2016)
DOI: 10.1038/nrd.2015.37
PMid:26868298

49. S. van Boheemen, M. de Graaf, C. Lauber, T. M. Bestebroer, V. S. Raj, A. M. Zaki, A. D. Osterhaus, B. L. Haagmans, A. E. Gorbalenya, E. J. Snijder and R. A. Fouchier: Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio, 3(6) (2012)

50. S. Agnihothram, R. Gopal, B. L. Yount, Jr., E. F. Donaldson, V. D. Menachery, R. L. Graham, T. D. Scobey, L. E. Gralinski, M. R. Denison, M. Zambon and R. S. Baric: Evaluation of serologic and antigenic relationships between middle eastern respiratory syndrome coronavirus and other coronaviruses to develop vaccine platforms for the rapid response to emerging coronaviruses. J Infect Dis, 209(7), 995-1006 (2014)
DOI: 10.1093/infdis/jit609
PMid:24253287 PMCid:PMC3952667

51. H. Mou, V. S. Raj, F. J. van Kuppeveld, P. J. Rottier, B. L. Haagmans and B. J. Bosch: The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J Virol, 87(16), 9379-83 (2013)
DOI: 10.1128/JVI.01277-13
PMid:23785207 PMCid:PMC3754068

52. N. M. Okba, V. S. Raj and B. L. Haagmans: Middle East respiratory syndrome coronavirus vaccines: current status and novel approaches. Curr Opin Virol, 23, 49-58 (2017)
DOI: 10.1016/j.coviro.2017.03.007
PMid:28412285

53. S. Jiang, L. Lu, L. Du and A. K. Debnath: A predicted receptor-binding and critical neutralizing domain in S protein of the novel human coronavirus HCoV-EMC. J Infect, 66(5), 464-6 (2013)
DOI: 10.1016/j.jinf.2012.12.003
PMid:23266463

54. S. Gierer, S. Bertram, F. Kaup, F. Wrensch, A. Heurich, A. Kramer-Kuhl, K. Welsch, M. Winkler, B. Meyer, C. Drosten, U. Dittmer, T. von Hahn, G. Simmons, H. Hofmann and S. Pohlmann: The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol, 87(10), 5502-11 (2013)
DOI: 10.1128/JVI.00128-13
PMid:23468491 PMCid:PMC3648152

55. G. Lu, Y. Hu, Q. Wang, J. Qi, F. Gao, Y. Li, Y. Zhang, W. Zhang, Y. Yuan, J. Bao, B. Zhang, Y. Shi, J. Yan and G. F. Gao: Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature, 500(7461), 227-31 (2013)
DOI: 10.1038/nature12328
PMid:23831647

56. V. S. Raj, H. Mou, S. L. Smits, D. H. Dekkers, M. A. Muller, R. Dijkman, D. Muth, J. A. Demmers, A. Zaki, R. A. Fouchier, V. Thiel, C. Drosten, P. J. Rottier, A. D. Osterhaus, B. J. Bosch and B. L. Haagmans: Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 495(7440), 251-4 (2013)
DOI: 10.1038/nature12005
PMid:23486063

57. L. Jiang, N. Wang, T. Zuo, X. Shi, K. M. Poon, Y. Wu, F. Gao, D. Li, R. Wang, J. Guo, L. Fu, K. Y. Yuen, B. J. Zheng, X. Wang and L. Zhang: Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med, 6(234), 234ra59 (2014)

58. J. Kameoka, T. Tanaka, Y. Nojima, S. F. Schlossman and C. Morimoto: Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science, 261(5120), 466-9 (1993)
DOI: 10.1126/science.8101391
PMid:8101391

59. C. Gakis: Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role. Eur Respir J, 9(4), 632-3 (1996)
DOI: 10.1183/09031936.96.09040632
PMid:8726922

60. W. A. Weihofen, J. Liu, W. Reutter, W. Saenger and H. Fan: Crystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface. J Biol Chem, 279(41), 43330-5 (2004)
DOI: 10.1074/jbc.M405001200
PMid:15213224

61. H. B. Rasmussen, S. Branner, F. C. Wiberg and N. Wagtmann: Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol, 10(1), 19-25 (2003)
DOI: 10.1038/nsb882
PMid:12483204

62. K. Ohnuma, B. L. Haagmans, R. Hatano, V. S. Raj, H. Mou, S. Iwata, N. H. Dang, B. J. Bosch and C. Morimoto: Inhibition of Middle East respiratory syndrome coronavirus infection by anti-CD26 monoclonal antibody. J Virol, 87(24), 13892-9 (2013)
DOI: 10.1128/JVI.02448-13
PMid:24067970 PMCid:PMC3838260

63. H. A. Mohd, J. A. Al-Tawfiq and Z. A. Memish: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) origin and animal reservoir. Virol J, 13, 87 (2016)

64. Z. A. Memish, A. I. Zumla, R. F. Al-Hakeem, A. A. Al-Rabeeah and G. M. Stephens: Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med, 368(26), 2487-94 (2013)
DOI: 10.1056/NEJMoa1303729
PMid:23718156

65. C. Drosten, M. Seilmaier, V. M. Corman, W. Hartmann, G. Scheible, S. Sack, W. Guggemos, R. Kallies, D. Muth, S. Junglen, M. A. Muller, W. Haas, H. Guberina, T. Rohnisch, M. Schmid-Wendtner, S. Aldabbagh, U. Dittmer, H. Gold, P. Graf, F. Bonin, A. Rambaut and C. M. Wendtner: Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis, 13(9), 745-51 (2013)
DOI: 10.1016/S1473-3099(13)70154-3

66. B. Guery, J. Poissy, L. el Mansouf, C. Sejourne, N. Ettahar, X. Lemaire, F. Vuotto, A. Goffard, S. Behillil, V. Enouf, V. Caro, A. Mailles, D. Che, J. C. Manuguerra, D. Mathieu, A. Fontanet, S. van der Werf and M. E.-C. s. group: Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet, 381(9885), 2265-72 (2013)
DOI: 10.1016/S0140-6736(13)60982-4

67. R. P. Dong, K. Tachibana, M. Hegen, S. Scharpe, D. Cho, S. F. Schlossman and C. Morimoto: Correlation of the epitopes defined by anti-CD26 mAbs and CD26 function. Mol Immunol, 35(1), 13-21 (1998)
DOI: 10.1016/S0161-5890(98)80013-8

68. T. Inamoto, T. Yamada, K. Ohnuma, S. Kina, N. Takahashi, T. Yamochi, S. Inamoto, Y. Katsuoka, O. Hosono, H. Tanaka, N. H. Dang and C. Morimoto: Humanized anti-CD26 monoclonal antibody as a treatment for malignant mesothelioma tumors. Clin Cancer Res, 13(14), 4191-200 (2007)
DOI: 10.1158/1078-0432.CCR-07-0110
PMid:17634548

69. N. Wang, X. Shi, L. Jiang, S. Zhang, D. Wang, P. Tong, D. Guo, L. Fu, Y. Cui, X. Liu, K. C. Arledge, Y. H. Chen, L. Zhang and X. Wang: Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res, 23(8), 986-93 (2013)
DOI: 10.1038/cr.2013.92
PMid:23835475 PMCid:PMC3731569

70. E. Angevin, N. Isambert, V. Trillet-Lenoir, B. You, J. Alexandre, G. Zalcman, P. Vielh, F. Farace, F. Valleix, T. Podoll, Y. Kuramochi, I. Miyashita, O. Hosono, N. H. Dang, K. Ohnuma, T. Yamada, Y. Kaneko and C. Morimoto: First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers. Br J Cancer, 116(9), 1126-1134 (2017)
DOI: 10.1038/bjc.2017.62
PMid:28291776 PMCid:PMC5418443

71. J. C. Szepietowski and A. Reich: Pruritus in psoriasis: An update. Eur J Pain, 20(1), 41-6 (2016)
DOI: 10.1002/ejp.768
PMid:26415584

72. G. Yosipovitch, A. Goon, J. Wee, Y. H. Chan and C. L. Goh: The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol, 143(5), 969-73 (2000)
DOI: 10.1046/j.1365-2133.2000.03829.x
PMid:11069504

73. J. C. Szepietowski, A. Reich and B. Wisnicka: Pruritus and psoriasis. Br J Dermatol, 151(6), 1284 (2004)
DOI: 10.1111/j.1365-2133.2004.06299.x
PMid:15606540

74. S. E. Chang, S. S. Han, H. J. Jung and J. H. Choi: Neuropeptides and their receptors in psoriatic skin in relation to pruritus. Br J Dermatol, 156(6), 1272-7 (2007)
DOI: 10.1111/j.1365-2133.2007.07935.x
PMid:17535226

75. B. Amatya, G. Wennersten and K. Nordlind: Patients’ perspective of pruritus in chronic plaque psoriasis: a questionnaire-based study. J Eur Acad Dermatol Venereol, 22(7), 822-6 (2008)
DOI: 10.1111/j.1468-3083.2008.02591.x
PMid:18422545

76. G. Stinco, G. Trevisan, F. Piccirillo, S. Pezzetta, E. Errichetti, N. di Meo, F. Valent and P. Patrone: Pruritus in chronic plaque psoriasis: a questionnaire-based study of 230 Italian patients. Acta Dermatovenerol Croat, 22(2), 122-8 (2014)

77. M. Nakamura, M. Toyoda and M. Morohashi: Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol, 149(4), 718-30 (2003)
DOI: 10.1046/j.1365-2133.2003.05586.x
PMid:14616362

78. A. S. Raut, R. H. Prabhu and V. B. Patravale: Psoriasis clinical implications and treatment: a review. Crit Rev Ther Drug Carrier Syst, 30(3), 183-216 (2013)
DOI: 10.1615/CritRevTherDrugCarrierSyst.2013005268
PMid:23614646

79. A. Thielitz, D. Reinhold, R. Vetter, U. Bank, M. Helmuth, R. Hartig, S. Wrenger, I. Wiswedel, U. Lendeckel, T. Kahne, K. Neubert, J. Faust, C. C. Zouboulis, S. Ansorge and H. Gollnick: Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation. J Invest Dermatol, 127(5), 1042-51 (2007)
DOI: 10.1038/sj.jid.5700439
PMid:16778789

80. M. Novelli, P. Savoia, M. T. Fierro, A. Verrone, P. Quaglino and M. G. Bernengo: Keratinocytes express dipeptidyl-peptidase IV (CD26) in benign and malignant skin diseases. Br J Dermatol, 134(6), 1052-6 (1996)
DOI: 10.1111/j.1365-2133.1996.tb07941.x
DOI: 10.1046/j.1365-2133.1996.d01-900.x
PMid:8763423

81. R. G. van Lingen, P. C. van de Kerkhof, M. M. Seyger, E. M. de Jong, D. W. van Rens, M. K. Poll, P. L. Zeeuwen and P. E. van Erp: CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes. Br J Dermatol, 158(6), 1264-72 (2008)
DOI: 10.1111/j.1365-2133.2008.08515.x
PMid:18384439

82. M. Lynch, A. M. Tobin, T. Ahern, D. O’Shea and B. Kirby: Sitagliptin for severe psoriasis. Clin Exp Dermatol, 39(7), 841-2 (2014)
DOI: 10.1111/ced.12408
PMid:25154439

83. T. Nishioka, M. Shinohara, N. Tanimoto, C. Kumagai and K. Hashimoto: Sitagliptin, a dipeptidyl peptidase-IV inhibitor, improves psoriasis. Dermatology, 224(1), 20-1 (2012)
DOI: 10.1159/000333358
PMid:22056790

84. K. Ohnuma, O. Hosono, N. H. Dang and C. Morimoto: Dipeptidyl peptidase in autoimmune pathophysiology. Adv Clin Chem, 53, 51-84 (2011)
DOI: 10.1016/B978-0-12-385855-9.00003-5
PMid:21404914

85. M. Diani, G. Altomare and E. Reali: T cell responses in psoriasis and psoriatic arthritis. Autoimmun Rev, 14(4), 286-92 (2015)
DOI: 10.1016/j.autrev.2014.11.012
PMid:25445403

86. J. Baliwag, D. H. Barnes and A. Johnston: Cytokines in psoriasis. Cytokine, 73(2), 342-50 (2015)
DOI: 10.1016/j.cyto.2014.12.014
PMid:25585875 PMCid:PMC4437803

87. M. P. Schon and W. H. Boehncke: Psoriasis. N Engl J Med, 352(18), 1899-912 (2005)
DOI: 10.1056/NEJMra041320
PMid:15872205

88. E. Komiya, R. Hatano, H. Otsuka, T. Itoh, H. Yamazaki, T. Yamada, N. H. Dang, M. Tominaga, Y. Suga, U. Kimura, K. Takamori, C. Morimoto and K. Ohnuma: A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus. J Dermatol Sci, 86(3), 212-221 (2017)
DOI: 10.1016/j.jdermsci.2017.03.005
PMid:28365081

89. K. Ohnuma, T. Saito, R. Hatano, O. Hosono, S. Iwata, N. H. Dang, H. Ninomiya and C. Morimoto: Comparison of two commercial ELISAs against an in-house ELISA for measuring soluble CD26 in human serum. J Clin Lab Anal, 29(2), 106-11 (2015)
DOI: 10.1002/jcla.21736
PMid:24687574

90. A. Sedo and R. Malik: Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities? Biochim Biophys Acta, 1550(2), 107-16 (2001)

91. C. De Felipe, J. F. Herrero, J. A. O’Brien, J. A. Palmer, C. A. Doyle, A. J. Smith, J. M. Laird, C. Belmonte, F. Cervero and S. P. Hunt: Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature, 392(6674), 394-7 (1998)
DOI: 10.1038/32904
PMid:9537323

92. F. O. Nestle, P. Di Meglio, J. Z. Qin and B. J. Nickoloff: Skin immune sentinels in health and disease. Nat Rev Immunol, 9(10), 679-91 (2009)
DOI: 10.1038/nri2622

93. T. Akiyama and E. Carstens: Neural processing of itch. Neuroscience, 250, 697-714 (2013)
DOI: 10.1016/j.neuroscience.2013.07.035
PMid:23891755 PMCid:PMC3772667

94. L. van der Fits, S. Mourits, J. S. Voerman, M. Kant, L. Boon, J. D. Laman, F. Cornelissen, A. M. Mus, E. Florencia, E. P. Prens and E. Lubberts: Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol, 182(9), 5836-45 (2009)
DOI: 10.4049/jimmunol.0802999
PMid:19380832

95. K. Sakai, K. M. Sanders, M. R. Youssef, K. M. Yanushefski, L. Jensen, G. Yosipovitch and T. Akiyama: Mouse model of imiquimod-induced psoriatic itch. Pain, 157(11), 2536-2543 (2016)
DOI: 10.1097/j.pain.0000000000000674
PMid:27437787 PMCid:PMC5069152

96. C. Remrod, S. Lonne-Rahm and K. Nordlind: Study of substance P and its receptor neurokinin-1 in psoriasis and their relation to chronic stress and pruritus. Arch Dermatol Res, 299(2), 85-91 (2007)
DOI: 10.1007/s00403-007-0745-x
PMid:17370082

97. B. Amatya, K. Nordlind and C. F. Wahlgren: Responses to intradermal injections of substance P in psoriasis patients with pruritus. Skin Pharmacol Physiol, 23(3), 133-8 (2010)
DOI: 10.1159/000270385
PMid:20051714

98. T. Miyagaki, M. Sugaya, H. Suga, S. Morimura, M. Kamata, H. Ohmatsu, H. Fujita, Y. Asano, Y. Tada, T. Kadono and S. Sato: Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis, cutaneous T-cell lymphoma and psoriasis in combination with serum thymus and activation-regulated chemokine levels. J Eur Acad Dermatol Venereol, 27(1), 19-24 (2013)
DOI: 10.1111/j.1468-3083.2011.04340.x
PMid:22077186

99. R. G. van Lingen, M. K. Poll, M. M. Seyger, E. M. de Jong, P. C. van de Kerkhof and P. E. van Erp: Distribution of dipeptidyl-peptidase IV on keratinocytes in the margin zone of a psoriatic lesion: a comparison with hyperproliferation and aberrant differentiation markers. Arch Dermatol Res, 300(10), 561-7 (2008)
DOI: 10.1007/s00403-008-0862-1
PMid:18496701

100. D. J. Drucker: Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care, 26(10), 2929-40 (2003)
DOI: 10.2337/diacare.26.10.2929
PMid:14514604

101. R. Barreira da Silva, M. E. Laird, N. Yatim, L. Fiette, M. A. Ingersoll and M. L. Albert: Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol, 16(8), 850-8 (2015)
DOI: 10.1038/ni.3201
PMid:26075911

102. P. Proost, E. Schutyser, P. Menten, S. Struyf, A. Wuyts, G. Opdenakker, M. Detheux, M. Parmentier, C. Durinx, A.-M. Lambeir, J. Neyts, S. Liekens, P. C. Maudgal, A. Billiau and J. Van Damme: Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties. Blood, 98(13), 3554-3561 (2001)
DOI: 10.1182/blood.V98.13.3554
PMid:11739156

103. P. van der Bruggen, C. Traversari, P. Chomez, C. Lurquin, E. De Plaen, B. Van den Eynde, A. Knuth and T. Boon: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science, 254(5038), 1643-7 (1991)
DOI: 10.1126/science.1840703
PMid:1840703

104. M. Liu, S. Guo and J. K. Stiles: The emerging role of CXCL10 in cancer. Oncol Lett, 2(4), 583-589 (2011)

105. J. R. Groom and A. D. Luster: CXCR3 in T cell function. Exp Cell Res, 317(5), 620-31 (2011)
DOI: 10.1016/j.yexcr.2010.12.017
PMid:21376175 PMCid:PMC3065205

106. M. A. Koch, G. Tucker-Heard, N. R. Perdue, J. R. Killebrew, K. B. Urdahl and D. J. Campbell: The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol, 10(6), 595-602 (2009)
DOI: 10.1038/ni.1731
PMid:19412181 PMCid:PMC2712126

107. Z. Shi, Y. Okuno, M. Rifa’i, A. T. Endharti, K. Akane, K. Isobe and H. Suzuki: Human CD8+CXCR3+ T cells have the same function as murine CD8+CD122+ Treg. Eur J Immunol, 39(8), 2106-19 (2009)
DOI: 10.1002/eji.200939314
PMid:19609979

108. R. Hatano, K. Ohnuma, H. Otsuka, E. Komiya, I. Taki, S. Iwata, N. H. Dang, K. Okumura and C. Morimoto: CD26-mediated induction of EGR2 and IL-10 as potential regulatory mechanism for CD26 costimulatory pathway. J Immunol, 194(3), 960-72 (2015)
DOI: 10.4049/jimmunol.1402143
PMid:25548232

109. T. Okamura, K. Fujio, M. Shibuya, S. Sumitomo, H. Shoda, S. Sakaguchi and K. Yamamoto: CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci U S A, 106(33), 13974-9 (2009)
DOI: 10.1073/pnas.0906872106
PMid:19666526 PMCid:PMC2729005

110. B. Huard, P. Prigent, F. Pages, D. Bruniquel and F. Triebel: T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol, 26(5), 1180-6 (1996)
DOI: 10.1002/eji.1830260533
PMid:8647185

111. L. Macon-Lemaitre and F. Triebel: The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology, 115(2), 170-8 (2005)
DOI: 10.1111/j.1365-2567.2005.02145.x
PMid:15885122 PMCid:PMC1782137

112. L. T. Nguyen and P. S. Ohashi: Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol, 15(1), 45-56 (2015)
DOI: 10.1038/nri3790
PMid:25534622

113. N. H. Dang, Y. Torimoto, S. F. Schlossman and C. Morimoto: Human CD4 helper T cell activation: functional involvement of two distinct collagen receptors, 1F7 and VLA integrin family. J Exp Med, 172(2), 649-52 (1990)
DOI: 10.1084/jem.172.2.649
PMid:2165129

114. V. J. Amatya, Y. Takeshima, K. Kushitani, T. Yamada, C. Morimoto and K. Inai: Overexpression of CD26/DPPIV in mesothelioma tissue and mesothelioma cell lines. Oncol Rep, 26(6), 1369-75 (2011)
DOI: 10.3892/or.2011.1449

115. K. Aoe, V. J. Amatya, N. Fujimoto, K. Ohnuma, O. Hosono, A. Hiraki, M. Fujii, T. Yamada, N. H. Dang, Y. Takeshima, K. Inai, T. Kishimoto and C. Morimoto: CD26 overexpression is associated with prolonged survival and enhanced chemosensitivity in malignant pleural mesothelioma. Clin Cancer Res, 18(5), 1447-56 (2012)
DOI: 10.1158/1078-0432.CCR-11-1990
PMid:22261805

116. T. Inamoto, T. Yamochi, K. Ohnuma, S. Iwata, S. Kina, S. Inamoto, M. Tachibana, Y. Katsuoka, N. H. Dang and C. Morimoto: Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27kip1 enhancement, and disruption of binding to the extracellular matrix. Clin Cancer Res, 12(11), 3470-7 (2006)
DOI: 10.1158/1078-0432.CCR-06-0361
PMid:16740772

117. M. Hayashi, H. Madokoro, K. Yamada, H. Nishida, C. Morimoto, M. Sakamoto and T. Yamada: A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition. Cancer Cell Int, 16, 35 (2016)

118. ClinicalTrials.gov: Clinical Study of YS110 in Patients With Malignant Pleural Mesothelioma. https://www.clinicaltrials.gov/ct2/show/NCT03177668?term=YS110&cond=Mesotheliomas+Pleural&rank=1, (2017)

119. C. Durinx, H. Neels, J. C. Van der Auwera, K. Naelaerts, S. Scharpe and I. De Meester: Reference values for plasma dipeptidyl-peptidase IV activity and their association with other laboratory parameters. Clin Chem Lab Med, 39(2), 155-9 (2001)
DOI: 10.1515/CCLM.2001.026
PMid:11341750

120. D. J. Drucker and M. A. Nauck: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 368(9548), 1696-705 (2006)
DOI: 10.1016/S0140-6736(06)69705-5

121. T. Okamoto, S. Iwata, H. Yamazaki, R. Hatano, E. Komiya, N. H. Dang, K. Ohnuma and C. Morimoto: CD9 negatively regulates CD26 expression and inhibits CD26-mediated enhancement of invasive potential of malignant mesothelioma cells. PLoS ONE, 9(1), e86671 (2014)
DOI: 10.1371/journal.pone.0086671
PMid:24466195 PMCid:PMC3900581

122. E. Komiya, K. Ohnuma, H. Yamazaki, R. Hatano, S. Iwata, T. Okamoto, N. H. Dang, T. Yamada and C. Morimoto: CD26-mediated regulation of periostin expression contributes to migration and invasion of malignant pleural mesothelioma cells. Biochem Biophys Res Commun, 447(4), 609-15 (2014)
DOI: 10.1016/j.bbrc.2014.04.037
PMid:24747072

123. L. Morra and H. Moch: Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update. Virchows Arch, 459(5), 465-75 (2011)
DOI: 10.1007/s00428-011-1151-5
PMid:21997759 PMCid:PMC3205268

124. J. Yamamoto, K. Ohnuma, R. Hatano, T. Okamoto, E. Komiya, H. Yamazaki, S. Iwata, N. H. Dang, K. Aoe, T. Kishimoto, T. Yamada and C. Morimoto: Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma. Br J Cancer, 110(9), 2232-45 (2014)
DOI: 10.1038/bjc.2014.151
PMid:24743707 PMCid:PMC4007235

125. K. Ohnuma, R. Hatano, H. Yamazaki, Y. Kaneko, N. H. Dang and C. Morimoto: CD26-targeted therapy: a new horizon in malignant pleural mesothelioma management. In: Horizons in Cancer Research. Ed S. H. Wanatabe. Nova Science Publishers, Inc., Hauppauge, NY (2017)

126. K. Yamada, M. Hayashi, W. Du, K. Ohnuma, M. Sakamoto, C. Morimoto and T. Yamada: Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect. Cancer Cell Int, 9, 17 (2009)

127. K. Yamada, M. Hayashi, H. Madokoro, H. Nishida, W. Du, K. Ohnuma, M. Sakamoto, C. Morimoto and T. Yamada: Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription. PLoS One, 8(4), e62304 (2013)
DOI: 10.1371/journal.pone.0062304
PMid:23638030 PMCid:PMC3639274

128. P. A. Havre, M. Abe, Y. Urasaki, K. Ohnuma, C. Morimoto and N. H. Dang: CD26 expression on T cell lines increases SDF-1-alpha-mediated invasion. Br J Cancer, 101(6), 983-91 (2009)
DOI: 10.1038/sj.bjc.6605236
PMid:19654580 PMCid:PMC2743358

129. D. Droz, D. Zachar, L. Charbit, J. Gogusev, Y. Chretein and L. Iris: Expression of the human nephron differentiation molecules in renal cell carcinomas. Am J Pathol, 137(4), 895-905 (1990)

130. T. Stange, U. Kettmann and H. J. Holzhausen: Immunoelectron microscopic demonstration of the membrane proteases aminopeptidase N/CD13 and dipeptidyl peptidase IV/CD26 in normal and neoplastic renal parenchymal tissues and cells. Eur J Histochem, 44(2), 157-64 (2000)

131. B. Bauvois, I. De Meester, J. Dumont, D. Rouillard, H. X. Zhao and E. Bosmans: Constitutive expression of CD26/dipeptidylpeptidase IV on peripheral blood B lymphocytes of patients with B chronic lymphocytic leukaemia. Br J Cancer, 79(7-8), 1042-8 (1999)

132. N. H. Dang, U. Aytac, K. Sato, S. O’Brien, J. Melenhorst, C. Morimoto, A. J. Barrett and J. J. Molldrem: T-large granular lymphocyte lymphoproliferative disorder: expression of CD26 as a marker of clinically aggressive disease and characterization of marrow inhibition. Br J Haematol, 121(6), 857-65 (2003)
DOI: 10.1046/j.1365-2141.2003.04365.x
PMid:12786796

133. A. Carbone, M. Cozzi, A. Gloghini and A. Pinto: CD26/dipeptidyl peptidase IV expression in human lymphomas is restricted to CD30-positive anaplastic large cell and a subset of T-cell non-Hodgkin’s lymphomas. Hum Pathol, 25(12), 1360-5 (1994)
DOI: 10.1016/0046-8177(94)90098-1

134. A. Carbone, A. Gloghini, V. Zagonel, D. Aldinucci, V. Gattei, M. Degan, S. Improta, R. Sorio, S. Monfardini and A. Pinto: The expression of CD26 and CD40 ligand is mutually exclusive in human T-cell non-Hodgkin’s lymphomas/leukemias. Blood, 86(12), 4617-26 (1995)

135. K. Sato and N. H. Dang: CD26: a novel treatment target for T-cell lymphoid malignancies? (Review). Int J Oncol, 22(3), 481-97 (2003)

136. U. Aytac, F. X. Claret, L. Ho, K. Sato, K. Ohnuma, G. B. Mills, F. Cabanillas, C. Morimoto and N. H. Dang: Expression of CD26 and its associated dipeptidyl peptidase IV enzyme activity enhances sensitivity to doxorubicin-induced cell cycle arrest at the G(2)/M checkpoint. Cancer Res, 61(19), 7204-10 (2001)

137. U. Aytac, K. Sato, T. Yamochi, T. Yamochi, K. Ohnuma, G. B. Mills, C. Morimoto and N. H. Dang: Effect of CD26/dipeptidyl peptidase IV on Jurkat sensitivity to G2/M arrest induced by topoisomerase II inhibitors. Br J Cancer, 88(3), 455-62 (2003)
DOI: 10.1038/sj.bjc.6600791
PMid:12569391 PMCid:PMC2747550

138. K. Sato, U. Aytac, T. Yamochi, T. Yamochi, K. Ohnuma, K. S. McKee, C. Morimoto and N. H. Dang: CD26/dipeptidyl peptidase IV enhances expression of topoisomerase IIα and sensitivity to apoptosis induced by topoisomerase II inhibitors. Br J Cancer, 89(7), 1366-74 (2003)
DOI: 10.1038/sj.bjc.6601253
PMid:14520473 PMCid:PMC2394325

139. T. Yamochi, T. Yamochi, U. Aytac, T. Sato, K. Sato, K. Ohnuma, K. S. McKee, C. Morimoto and N. H. Dang: Regulation of p38 phosphorylation and topoisomerase IIα expression in the B-cell lymphoma line Jiyoye by CD26/dipeptidyl peptidase IV is associated with enhanced in vitro and in vivo sensitivity to doxorubicin. Cancer Res, 65(5), 1973-83 (2005)
DOI: 10.1158/0008-5472.CAN-04-2611
PMid:15753397

140. T. Oravecz, M. Pall, G. Roderiquez, M. D. Gorrell, M. Ditto, N. Y. Nguyen, R. Boykins, E. Unsworth and M. A. Norcross: Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage. J Exp Med, 186(11), 1865-72 (1997)
DOI: 10.1084/jem.186.11.1865
PMid:9382885 PMCid:PMC2199148

141. P. Proost, S. Struyf, D. Schols, G. Opdenakker, S. Sozzani, P. Allavena, A. Mantovani, K. Augustyns, G. Bal, A. Haemers, A. M. Lambeir, S. Scharpe, J. Van Damme and I. De Meester: Truncation of macrophage-derived chemokine by CD26/ dipeptidyl-peptidase IV beyond its predicted cleavage site affects chemotactic activity and CC chemokine receptor 4 interaction. J Biol Chem, 274(7), 3988-93 (1999)
DOI: 10.1074/jbc.274.7.3988
PMid:9933589

142. R. Pang, W. L. Law, A. C. Chu, J. T. Poon, C. S. Lam, A. K. Chow, L. Ng, L. W. Cheung, X. R. Lan, H. Y. Lan, V. P. Tan, T. C. Yau, R. T. Poon and B. C. Wong: A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell, 6(6), 603-15 (2010)
DOI: 10.1016/j.stem.2010.04.001
PMid:20569697

143. J. H. Jang, L. Baerts, Y. Waumans, I. De Meester, Y. Yamada, P. Limani, I. Gil-Bazo, W. Weder and W. Jungraithmayr: Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. Clin Exp Metastasis, 32(7), 677-87 (2015)
DOI: 10.1007/s10585-015-9736-z
PMid:26233333

144. U. Yamaguchi, R. Nakayama, K. Honda, H. Ichikawa, T. Hasegawa, M. Shitashige, M. Ono, A. Shoji, T. Sakuma, H. Kuwabara, Y. Shimada, M. Sasako, T. Shimoda, A. Kawai, S. Hirohashi and T. Yamada: Distinct gene expression-defined classes of gastrointestinal stromal tumor. J Clin Oncol, 26(25), 4100-8 (2008)
DOI: 10.1200/JCO.2007.14.2331
PMid:18757323

145. V. K. Hopsu-Havu and G. G. Glenner: A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemie, 7(3), 197-201 (1966)
DOI: 10.1007/BF00577838
PMid:5959122

146. C. A. Abbott, E. Baker, G. R. Sutherland and G. W. McCaughan: Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics, 40(5), 331-8 (1994)
DOI: 10.1007/BF01246674
PMid:7927537

147. M. E. Morrison, S. Vijayasaradhi, D. Engelstein, A. P. Albino and A. N. Houghton: A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med, 177(4), 1135-43 (1993)
DOI: 10.1084/jem.177.4.1135
PMid:8096237

148. S. S. Farag, S. Srivastava, S. Messina-Graham, J. Schwartz, M. J. Robertson, R. Abonour, K. Cornetta, L. Wood, A. Secrest, R. M. Strother, D. R. Jones and H. E. Broxmeyer: In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev, 22(7), 1007-15 (2013)
DOI: 10.1089/scd.2012.0636
PMid:23270493 PMCid:PMC3607909

149. P. Proost, S. Struyf, J. Van Damme, P. Fiten, E. Ugarte-Berzal and G. Opdenakker: Chemokine isoforms and processing in inflammation and immunity. J Autoimmun (2017)

150. K. Ohnuma, R. Hatano, T. Itoh, N. Iwao, N. H. Dang and C. Morimoto: Role of IL-26+CD26+CD4 T Cells in Pulmonary Chronic Graft-Versus-Host Disease and Treatment with Caveolin-1-Ig Fc Conjugate. Crit Rev Immunol, 36(3), 239-267 (2016)
DOI: 10.1615/CritRevImmunol.2016018772
PMid:28008806

151. F. I. Ghani, H. Yamazaki, S. Iwata, T. Okamoto, K. Aoe, K. Okabe, Y. Mimura, N. Fujimoto, T. Kishimoto, T. Yamada, C. W. Xu and C. Morimoto: Identification of cancer stem cell markers in human malignant mesothelioma cells. Biochem Biophys Res Commun, 404(2), 735-42 (2011)
DOI: 10.1016/j.bbrc.2010.12.054
PMid:21163253

152. H. Yamazaki, M. Naito, F. I. Ghani, N. H. Dang, S. Iwata and C. Morimoto: Characterization of cancer stem cell properties of CD24 and CD26-positive human malignant mesothelioma cells. Biochem Biophys Res Commun, 419(3), 529-36 (2012)
DOI: 10.1016/j.bbrc.2012.02.054
PMid:22369943

153. H. Herrmann, I. Sadovnik, S. Cerny-Reiterer, T. Rulicke, G. Stefanzl, M. Willmann, G. Hoermann, M. Bilban, K. Blatt, S. Herndlhofer, M. Mayerhofer, B. Streubel, W. R. Sperr, T. L. Holyoake, C. Mannhalter and P. Valent: Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood, 123(25), 3951-62 (2014)
DOI: 10.1182/blood-2013-10-536078
PMid:24778155

154. S. Davies, A. Beckenkamp and A. Buffon: CD26 a cancer stem cell marker and therapeutic target. Biomed Pharmacother, 71, 135-8 (2015)
DOI: 10.1016/j.biopha.2015.02.031
PMid:25960228

155. R. Hatano, T. Yamada, S. Matsuoka, S. Iwata, H. Yamazaki, E. Komiya, T. Okamoto, N. H. Dang, K. Ohnuma and C. Morimoto: Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin-fixed tissue. Diagn Pathol, 9, 30-42 (2014)
DOI: 10.1186/1746-1596-9-30
PMid:24502396 PMCid:PMC3944398

156. K. Ohnuma, R. Hatano and C. Morimoto: DPP4 in anti-tumor immunity: going beyond the enzyme. Nat Immunol, 16(8), 791-2 (2015)
DOI: 10.1038/ni.3210
PMid:26194276

Abbreviation: AA, amino acid; ADA, adenosine deaminase; ADCC, antibody-dependent cellular cytotoxicity; aGVHD, acute graft-versus-host disease; alloHSCT, allogeneic hematopoietic stem cell transplantation; AP-1, activator protein-1; APCs, antigen presenting cells; A20-luc, luciferase-transfected A20 cell; B6 WT, parental C57BL/6 mice; Cav-Ig, soluble Fc fusion proteins containing the N-terminal domain of caveolin-1; CB, cord blood; CD26KO, CD26 knockout; cGVHD, chronic graft-versus-host disease; CRC, colorectal cancer; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; ΔCNS-77 Tg mice, mice carrying human IFNG transgene with deleting IL26 transcription; DPPIV, dipeptidyl peptidase IV; ECM, extracellular matrix; EGR2, early growth response 2; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial to mesenchymal transition; ERK, extracellular signal-regulated kinase; FIH, first-in-human; GIST, gastrointestinal stromal tumors; GVHD, graft-versus-host disease; GVL, graft-versus-leukemia; HuCB, human umbilical cord blood; IBD, inflammatory bowel diseases; i.d., intradermal injection; IFN, interferon; IL, interleukin; IMQ, imiquimod; JKT-hCD26WT, Jurkat cells transfected with full-length human CD26/DPPIV; LAG3, lymphocyte activation gene-3; LBL/ALL, lymphoblastic lymphoma/acute lymphoblastic leukemia: mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MERS-CoV, Middle East respiratory syndrome coronavirus; MERS-CoV S1-Fc, S1 domain of MERS-CoV fused to the Fc region of human IgG; MPM, malignant pleural mesothelioma; NFAT, nuclear factor of activated T cells; NOG, NOD/Shi-scidIL2rγnull; OB, obliterative bronchiolitis; PBL, peripheral blood lymphocyte; PD-1, programmed cell death 1; PSO, psoriasis; RA, rheumatoid arthritis; RBD, receptor binding domain; RCC, renal cell carcinoma; RECIST, response evaluation criteria in solid tumors; sCD26, soluble CD26; sDPPIV, soluble dipeptidyl peptidase IV; siRNA, small interfering RNA; SP, substance P; SSTR4, somatostatin receptor 4; Tg, transgenic; T-LGL, T-large granular lymphocyte; TME, tumor microenvironment; TNF, tumor necrosis factor; Tr1, Type 1 regulatory T cells; WHO, World Health Organization; 190-IFNG Tg mice, mice carrying human IFNG and IL26 transgene

Key Words CD26, DPPIV, Caveolin-1, Humanized anti-CD26 monoclonal antibody, Graft-versus-host disease, Malignant pleural mesothelioma, Review

Send correspondence to: Kei Ohnuma, Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan, Tel: 81-3-3868-2310, Fax: 81-3-3868-2310, E-mail: kohnuma@juntendo.ac.jp