Ординатура / Офтальмология / Английские материалы / Primary Intraocular Lymphoma_Chan, Gonzales_2007

124 Primary Intraocular Lymphoma

arthritis,71 inflammatory bowel disease,72 and multiple sclerosis.73 Evidence also exists on the involvement of chemokines and their receptors in cancer, including breast cancer metastasis,74 chronic lymphocytic leukemia,75 and B-cell NHL.76

Two chemokines involved in B-cell chemoattraction include CXCL12 (also known as SDF-1 (stromal derived factor-1, which binds to CXCR4 receptor on B-cells)) and CXCL13 (also known as BCA-1/BLC (B-cell specific chemokine, which binds to CXCR5 receptor on B-cells)). The interaction of CXCL13 with its receptor, CXCR5 on B-cells is necessary for the formation of germinal centers77 and for the germinal center B-cells to undergo somatic hypermutation and subsequent affinity maturation. After activation, these B-cells seem to become more responsive to CXCL12, thereby chemoattracting the B-cells out of the germinal center as these B-cells also express the receptor for CXCL12, CXCR4.

As the CNS, including the eye, is an immunologically privileged site, it remains an enigma as to why a lymphoma should involve this location. Chemokines and their receptors might provide some insights into the pathogenesis of PCNSL/PIOL. The expression of chemokine receptors on various tumor cells has been shown to be involved in their localization to certain sites.74,78 Similarly, chemokines have been shown to be involved in PCNSL and PIOL. At the NEI, we have shown that B-cell-attractive chemokines are expressed in the retinal tissues of patients with PIOL.79 Tissue provided from two enucleated eyes and one chorioretinal biopsy, all containing PIOL, and one normal autopsy eye were analyzed. Microdissection was performed on frozen sections of the ocular tissues to obtain either PIOL cells or retinal pigment epithelium (RPE). Reverse transcriptase (RT)-PCR was performed on the extracted RNA for PIOL cells as well as RPE cells that were adjacent to the PIOL cells and RPE cells that were located away from the tumor. PIOL cells were shown to express both B-cell chemokine receptors, CXCR5 and CXCR4, while adjacent RPE cells expressed CXCL13 and CXCL12. RPE tissue distant from tumor invasion also showed expression of CXCL13 mRNA that was more abundant than tumor-adjacent RPE tissue; distant RPE did not express mRNA for CXCL12. The more abundant expression of mRNA by distant RPE cells was of interest to us and could possibly be explained by three mechanisms. First, there could be downregulation of CXCL12 and CXCL13 in the

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tumor-adjacent RPE cells, perhaps after interaction with their respective chemokine receptors on the infiltrating lymphoma cells. Second, RPE cells adjacent to tumor are damaged or destroyed, while more distant RPE is intact. Finally, reactive inflammatory cells (T lymphocytes and macrophages) can also be admixed in the area of tumor infiltration. The RPE from the normal autopsy eye did not show mRNA expression of either CXCL12 or CXCL13. Therefore, deviant expression of chemokines by PIOL-susceptible RPE could be a means for the recruitment of malignant B-cells as well as their infiltration of areas with increased expression of such chemokines.

In a study of biopsy specimens from 24 patients with PCNSL (17 HIVnegative, three HIV-positive, and four with unknown HIV status), immunostaining for CXCL13 revealed that all the samples were positive for expression of the chemokine.80 Double immunostaining for CD20 (B- cell antigen) and CD31 (vascular endothelial antigen) on five biopsy specimens revealed that CXCL13 was expressed by the lymphoma and the vascular endothelial cells. There was no staining of normal, non-infiltrated brain tissue. Furthermore, immunostaining for CXCR5, CXCL13’s receptor, resulted in staining of the membranes of the lymphoma cells. More recently, Jahnke and colleagues showed that in 29 biopsy specimens from PCNSL patients, CXCR4, CXCR5, and CCR7 were expressed only in the cytoplasm or nucleus, but not on the membrane of lymphoma cells.81 This was in contrast to lymphoma cells from peripheral-NHL biopsy specimens. These data could offer an explanation as to why PCNSL so rarely metastasizes.

There is a complex interaction between cells, their receptors, and signals (interleukins and chemokines), and this is involved not only in the homing of lymphomas to specific sites in the CNS (both cerebral and ocular), but also in their restriction to these sites and lack of metastasis. Although we do not understand precisely how chemokine and cytokine profiles are involved in the pathogenesis of all PCNSL/PIOLs, we are making progress in elucidating some of the mechanisms by which PIOL is able to make its home in the eye. We are currently examining murine PIOL models82 (see Chapter 13 – Animal Models of PIOL). Furthermore, we can attempt to interfere with these mechanisms to direct future therapeutic interventions.

126 Primary Intraocular Lymphoma

References

1.Schubert MS, Moss RB. (1992) Selective polysaccharide antibody deficiency in familial DiGeorge syndrome. Ann Allergy 69(3): 231–238.

2.Smith CA, Driscoll DA, Emanuel BS, et al. (1998) Increased prevalence of immunoglobulin A deficiency in patients with the chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin

Diagn Lab Immunol 5(3): 415–417.

3.Sullivan KE, Jawad AF, Randall P, et al. (1998) Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol 86(2): 141–146.

4.Trapani JA, Sutton VR. (2003) Granzyme B: pro-apoptotic, antiviral and antitumor functions. Curr Opin Immunol 15(5): 533–543.

5.Ashton-Rickardt PG. (2005) The granule pathway of programmed cell death. Crit Rev Immunol 25(3): 161–182.

6.Nishiyama A, Saito T, Abe S, Kumanishi T. (1989) An immunohistochemical analysis of T cells in primary B cell malignant lymphoma of the brain. Acta Neuropathol (Berl) 79(1): 27–29.

7.Bashir R, Chamberlain M, Ruby E, Hochberg FH. (1996) T-cell infiltration of primary CNS lymphoma. Neurology 46(2): 440–444.

8.Lopez JS, Chan CC, Burnier M, et al. (1991) Immunohistochemistry findings in primary intraocular lymphoma. Am J Ophthalmol 112(4): 472–474.

9.Char DH, Margolis L, Newman AB. (1981) Ocular reticulum cell sarcoma.

Am J Ophthalmol 91(4): 480–483.

10.Tuaillon N, Chan CC. (2001) Molecular analysis of primary central nervous system and primary intraocular lymphoma. Curr Mol Med 1(2): 259–272.

11.Coupland SE, Heimann H, Bechrakis NE. (2004) Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features. Graefes Arch Clin Exp Ophthalmol 242(11): 901–913.

12.Chan CC, Wallace DJ. (2004) Intraocular lymphoma: update on diagnosis and management. Cancer Control 11(5): 285–295.

13.Rosenberg SA, Terry WD. (1977) Passive immunotherapy of cancer in animals and man. Adv Cancer Res 25: 323–388.

14.Kedar E, Weiss DW. (1983) The in vitro generation of effector lymphocytes and their employment in tumor immunotherapy. Adv Cancer Res 38: 171–287.

15.Kawakami Y, Eliyahu S, Sakaguchi K, et al. (1994) Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2–restricted tumor infiltrating lymphocytes. J Exp Med 180(1): 347–352.

Immunology of PIOL 127

16.Yang D, Nakao M, Shichijo S, et al. (1999) Identification of a gene coding for a protein possessing shared tumor epitopes capable of inducing HLA-A24- restricted cytotoxic T lymphocytes in cancer patients. Cancer Res 59(16): 4056–4063.

17.Del Prete G. (1998) The concept of type-1 and type-2 helper T cells and their cytokines in humans. Int Rev Immunol, 16(3–4): 427–455.

18.Del Prete GF, De Carli M, Ricci M, Romagnani S. (1991) Helper activity for immunoglobulin synthesis of T helper type 1 (Th1) and Th2 human T cell clones: the help of Th1 clones is limited by their cytolytic capacity. J Exp Med 174(4): 809–813.

19.Fallarino F, Grohmann U, Bianchi R, et al. (2000) Th1 and Th2 cell clones to a poorly immunogenic tumor antigen initiate CD8+ T cell-dependent tumor eradication in vivo. J Immunol 165(10): 5495–5501.

20.Knutson KL, Disis ML. (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54(8): 721–728.

21.Knutson KL, Disis ML. (2005) Augmenting T helper cell immunity in cancer. Curr Drug Targets Immune Endocr Metabol Disord 5(4): 365–371.

22.Alvaro-Naranjo T, Lejeune M, Salvado-Usach MT, et al. (2005) Tumor-infil- trating cells as a prognostic factor in Hodgkin’s lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma 46(11): 1581–1591.

23.Whitcup SM, de Smet MD, Rubin BI, et al. (1993) Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 100: 1399–1406.

24.Davis JL, Solomon D, Nussenblatt RB, et al. (1992) Immunocytochemical staining of vitreous cells. Indications, techniques, and results. Ophthalmology 99(2): 250–256.

25.Zou W. (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5(4): 263–274.

26.Corthay A, Skovseth DK, Lundin KU, et al. (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22(3): 371–383.

27.Steinman RM. (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9: 271–296.

28.Chiodoni C, Paglia P, Stoppacciaro A, et al. (1999) Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J Exp Med 190(1): 125–133.

29.Preynat-Seauve O, Schuler P, Contassot E, et al. (2006) Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J Immunol 176(1): 61–67.

128Primary Intraocular Lymphoma

30.Steinbrink K, Wolfl M, Jonuleit H, et al. (1997) Induction of tolerance by IL- 10-treated dendritic cells. J Immunol 159(10): 4772–4780.

31.Chan CC, Whitcup SM, Solomon D, Nussenblatt RB. (1995) Interleukin-10 in the vitreous of primary intraocular lymphoma. Am J Ophthalmol 120(5): 671–673.

32.Merle-Beral H, Davi F, Cassoux N, et al. (2004) Biological diagnosis of primary intraocular lymphoma. Br J Haematol 124(4): 469–473.

33.Radford KJ, Vari F, Hart DN. (2005) Vaccine strategies to treat lymphoproliferative disorders. Pathology 37(6): 534–550.

34.Soussain C, Hoang-Xuan K, Levy V. (2004) Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. Bull Cancer 91(2): 189–192.

35.Brevet M, Garidi R, Gruson B, et al. (2005) First-line autologous stem cell transplantation in primary CNS lymphoma. Eur J Haematol 75(4): 288–292.

36.Lotze C, Schuler F, Kruger WH, et al. (2005) Combined immunoradiotherapy induces long-term remission of CNS relapse of peripheral, diffuse, large-cell lymphoma after allogeneic stem cell transplantation: case study. Neuro-oncol 7(4): 508–510.

37.Blay JY, Burdin N, Rousset F, et al. (1993) Serum interleukin-10 in nonHodgkin’s lymphoma: a prognostic factor. Blood 82(7): 2169–2174.

38.Bost KL, Bieligk SC, Jaffe BM. (1995) Lymphokine mRNA expression by transplantable murine B lymphocytic malignancies. Tumor-derived IL-10 as a possible mechanism for modulating the anti-tumor response. J Immunol 154(2): 718–729.

39.Whitcup SM, Stark-Vancs V, Wittes RE, et al. (1997) Association of inter- leukin-10 in the vitreous and cerebral spinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 115: 1157–1160.

40.Wolf LA, Reed GF, Buggage RR, et al. (2003) Vitreous cytokine levels. Ophthalmology 110(8): 1671–1672.

41.Chan CC, Shen DF. (1999) Newer methodologies in immunohistochemistry and diagnosis. In BenEzra, D. (ed), Uveitis Update, pp. 1–13, Karger, Basel.

42.Tilg H, Atkins MB, Dinarello CA, Mier JW. (1995) Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy. Cytokine 7(7): 734–739.

43.Daftarian PM, Kumar A, Kryworuchko M, Diaz-Mitoma F. (1996) IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha. J Immunol 157(1): 12–20.

44.Bogdan C, Vodovotz Y, Nathan C. (1991) Macrophage deactivation by interleukin 10. J Exp Med 174(6): 1549–1555.

Immunology of PIOL 129

45.D’Andrea A, Aste-Amezaga M, Valiante NM, et al. (1993) Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 178(3): 1041–1048.

46.de Waal Malefyt R, Haanen J, Spits H, et al. (1991) Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174(4): 915–924.

47.Petersson M, Charo J, Salazar-Onfray F, et al. (1998) Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)- 1/2 function in the prototype NK target YAC-1. J Immunol 161(5): 2099–2105.

48.Howard M, O’Garra A, Ishida H, et al. (1992) Biological properties of interleukin 10. J Clin Immunol 12(4): 239–247.

49.Mu W, Ouyang X, Agarwal A, et al. (2005) IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease. J Am Soc Nephrol 16(12): 3651–3660.

50.Duchmann R, Schmitt E, Knolle P, et al. (1996) Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol 26(4): 934–938.

51.Matsuda M, Salazar F, Petersson M, et al. (1994) Interleukin 10 pretreatment protects target cells from tumorand allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 180(6): 2371–2376.

52.Benjamin D, Knobloch TJ, Dayton MA. (1992) Human B-cell interleukin10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt’s lymphoma constitutively secrete large quantities of interleukin-10. Blood 80(5): 1289–1298.

53.Burdin N, Peronne C, Banchereau J, Rousset F. (1993) Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med 177(2): 295–304.

54.De Luca A, Antinori A, Cingolani A, et al. (1995) Evaluation of cerebrospinal fluid EBV-DNA and IL-10 as markers for in vivo diagnosis of AIDS-related primary central nervous system lymphoma [published erratum appears in Br J Haematol 1995 Dec; 91(4): 1035]. Br J Haematol 90(4): 844–849.

55.Salmaggi A, Eoli M, Corsini E, et al. (2000) Cerebrospinal fluid interleukin10 levels in primary central nervous system lymphoma: a possible marker of response to treatment? Ann Neurol 47(1): 137–138.

130Primary Intraocular Lymphoma

56.Yokota M, Takase H, Imai Y, et al. (2003) A case of intraocular malignant lymphoma diagnosed by immunoglobulin gene rearrangement and translocation, and IL-10/IL-6 ratio in the vitreous fluid. Nippon Ganka Gakkai Zasshi 107(5): 287–291.

57.Horn F, Henze C, Heidrich K. (2000) Interleukin-6 signal transduction and lymphocyte function. Immunobiology 202(2): 151–167.

58.Morse L, Chen D, Franklin D, et al. (1997) Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. Immunity 6(1): 47–56.

59.Hodge DR, Hurt EM, Farrar WL. (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16): 2502–2512.

60.Simpson RJ, Hammacher A, Smith DK, et al. (1997) Interleukin-6: struc- ture-function relationships. Protein Sci 6(5): 929–955.

61.Romano M, Sironi M, Toniatti C, et al. (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6(3): 315–325.

62.Hurst SM, Wilkinson TS, McLoughlin RM, et al. (2001) Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 14(6): 705–714.

63.Kopf M, Baumann H, Freer G, et al. (1994) Impaired immune and acutephase responses in interleukin-6–deficient mice. Nature 368(6469): 339–342.

64.Chai Z, Gatti S, Toniatti C, et al. (1996) Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6–deficient mice. J Exp Med 183(1): 311–316.

65.Murray PI, Hoekzema R, van Haren MA, et al. (1990) Aqueous humor inter- leukin-6 levels in uveitis. Invest Ophthalmol Vis Sci 31(5): 917–920.

66.Akpek EK, Maca SM, Christen WG, Foster CS. (1999) Elevated vitreous interleukin-10 level is not diagnostic of intraocular-central nervous system lymphoma. Ophthalmology 106(12): 2291–2295.

67.Buggage RR, Velez G, Myers-Powell B, et al. (1999) Primary intraocular lymphoma with a low interleukin 10 to interleukin 6 ratio and heterogeneous IgH gene rearrangement. Arch Opthalmol 117(9): 1239–1242.

68.Cassoux N, Merle-Beral H, Leblond V, et al. (2000) Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocul Immunol Inflamm 8(4): 243–250.

69.Velez G, Buggage R. (2001) Interleukin-10 and intraocular-central nervous system lymphoma. Ophthalmology 108(3): 427–428.

70.Zlotnik A, Yoshie O. (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2): 121–127.

Immunology of PIOL 131

71.Koch AE, Kunkel SL, Harlow LA, et al. (1994) Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 93(3): 921–928.

72.Danese S, Gasbarrini A. (2005) Chemokines in inflammatory bowel disease. J Clin Pathol 58(10): 1025–1027.

73.Sorensen TL, Tani M, Jensen J, et al. (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103(6): 807–815.

74.Muller A, Homey B, Soto H, et al. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824): 50–56.

75.Mohle R, Failenschmid C, Bautz F, Kanz L. (1999) Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia 13(12): 1954–1959.

76.Arai J, Yasukawa M, Yakushijin Y, et al. (2000) Stromal cells in lymph nodes attract B-lymphoma cells via production of stromal cell-derived factor-1.

Eur J Haematol 64(5): 323–332.

77.Forster R, Mattis AE, Kremmer E, et al. (1996) A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87(6): 1037–1047.

78.Mashino K, Sadanaga N, Yamaguchi H, et al. (2002) Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 62(10): 2937–2941.

79.Chan CC, Shen D, Hackett JJ, et al. (2003) Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma. Ophthalmology 110(2): 421–426.

80.Smith JR, Braziel RM, Paoletti S, et al. (2003) Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 101(3): 815–821.

81.Jahnke K, Coupland SE, Na IK, et al. (2005) Expression of the chemokine receptors CXCR4, CXCR5, and CCR7 in primary central nervous system lymphoma. Blood 106(1): 384–385.

82.Chan CC, Fischette M, Shen D, et al. (2005) Murine model of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 46(2): 415–419.