Cartilage proteoglycan-specific T cells as vectors of immunomodulatory biologicals in chronic proteoglycan-induced arthritis.
Systemic administration of agents that neutralize or antagonize Th1-mediated pro-inflammatory responses has been demonstrated to ameliorate inflammation in chronic autoimmune disease. However, systemic administration of such immunosuppressive biologicals causes serious side effects and has only limited success. To minimize these side effects, autoantigen-specific lymphocytes have been proposed as a carrier to deliver immunosuppressive agents to sites of inflammation. Here we studied the effects of primary cartilage proteoglycan-specific CD4+ T cells that were transduced using an efficient method of viral transduction with active genes encoding IL-1beta receptor antagonist, soluble TNF-alpha receptor-Ig, IL-4 or IL-10 in chronic proteoglycan-induced arthritis in mice. This is the first study describing such gene therapy using primary CD4+ T cells in a chronic arthritis. Moreover, the impact of proteoglycan-specific Th1, Th2 or naïve T cells was studied. Although proteoglycan-TCR transgenic CD4+ T cells can transfer arthritis to lymphopenic recipients, none of the proteoglycan-TCR transgenic T cell phenotypes that were tested induced worsening of arthritis in wild type hosts. Proteoglycan-specific T cells ameliorated arthritis when expressing the transduced IL-10 gene, and not when expressing the other transgenes/phenotypes. Although all of the tested biologicals can suppress in a wide range of different inflammatory disorders, especially IL-10 would therefore serve as a promising candidate to be used in cellular gene therapy for chronic arthritis.
Guichelaar
Teun
T
Division of Immunology, Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
ten Brink
Corlinda B
CB
van Kooten
Peter J
PJ
Berlo
Suzanne E
SE
Lafeber
Floris P
FP
Broeren
Chris P
CP
van Eden
Willem
W
Broere
Femke
F
D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002356:Cartilage / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011509:Proteoglycans / Q000009:adverse effects / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes
D018984:Epitopes, T-Lymphocyte; D007155:Immunologic Factors; D011509:Proteoglycans; D016753:Interleukin-10