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(Investigative Ophthalmology and Visual Science. 2007;48:3223-3229.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0008
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Impaired Th1/Tc1 Cytokine Production of Tumor-Infiltrating Lymphocytes in a Model of Primary Intraocular B-Cell Lymphoma

Valérie Touitou,1 Cécile Daussy,1 Bahram Bodaghi,2 Serge Camelo,3 Yvonne de Kozak,3 Phuc Lehoang,2 Marie-Christine Naud,3 Audrey Varin,1 Brigitte Thillaye-Goldenberg,3 Hélène Merle-Béral,4 Wolf Herman Fridman,1 Catherine Sautès-Fridman,1 and Sylvain Fisson1

1From the Immune Microenvironment and Tumors Group and 3Physiopathology of Eye Diseases Group, INSERM (Institut National de la Santé et de la Recherche Médicale) UMRS872, Université Pierre et Marie Curie-Paris, Université René Descartes-Paris, Centre de Recherche des Cordeliers, Paris, France; and the 2Departments of Ophthalmology and 4Hematology Hôpital de la Pitié-Salpêtrière, Paris, France.

PURPOSE. Primary intraocular lymphoma is a high-grade non-Hodgkin lymphoma with a pathogenesis that is still unclear. Microenvironment is known to be crucial in controlling tumor growth and maintenance. To study the immune microenvironment in intraocular lymphomas and to characterize the cytokine polarization of infiltrating T-lymphocytes, a new murine model of intraocular B-cell lymphoma was developed.

METHODS. Immunocompetent adult mice were injected intravitreally with a syngeneic lymphomatous B-cell line. Clinical, histologic, and flow cytometric analyses were performed to characterize the tumoral invasion and the immune infiltration. Cytokine production of ocular cells was investigated by RT-PCR and fluorescent immunoassay, with or without stimulation by anti-CD3+ anti-CD28 antibodies.

RESULTS. Intraocular lymphoma developed in eyes injected by lymphomatous B-cells. At day 19, the retina and the vitreous cavity were infiltrated by tumor cells. Up to 15% of living cells were T-lymphocytes. Cytokine profile analysis of the supernatant of ocular cells cultured ex vivo demonstrated the presence of IL10, IL6, IFN{gamma}, and TNF{alpha}. Stimulation of ocular cells with anti-CD3+ anti-CD28 antibodies increased the IFN{gamma} level and led to the induction of IL2 production, completing the type 1 (Th1/Tc1-like) pattern of cytokine expression observed. IL12p70 and IL4, potent Th1 or Th2 differentiating factors, were undetectable, even after stimulation.

CONCLUSIONS. The results suggest that T-cells from intraocular B-lymphomas are characterized by a Th1/Tc1-like profile that could be partially inhibited in vivo. These data raise the possibility of a T-cell immunostimulation to reactivate the Th1/Tc1-lymphocytes and improve intraocular antitumoral immunity.






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