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What are the basic hypotheses of the tolerogenic theory?

The tolerogenic theory posits that extracorporeal photopheresis (ECP) efficacy may be ascribed to the induction of immunologic tolerance. This tolerance may be achieved through one or more factors that occur following the reinfusion of cells induced to undergo apoptosis. The first factor is a modification in the antigen-presenting cell (APC) population. In the absence of danger signals, uptake of apoptotic cells can prevent the maturation of dendritic cells and inhibit their antigen presenting capacity.5,16 Induction of tolerance may also be mediated by increased production of TGF-beta and IL-10. 8,10,14 Conversely, a decrease in pro-inflammatory cytokines such as TNF and IL-12 has also been shown after ECP. 1,5 Another possible factor is the induction of regulatory T-cells, or Tregs. Regulatory T-cells have been shown to contribute to tolerance via several actions, including controlling APC maturation and effector cell responses. 2,9,15,17

References

  1. Albert ML. Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol. 2004;4:223-31.
  2. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6(4):353-360.
  3. Berger CL, Hanlon D, Kanada D, Girardi M, Edelson RL. Transimmunization, a novel approach for tumor immunotherapy. Transfus Apher Sci. 2002;26(3):205-216.
  4. Biagi E, Di Biaso I, Leoni V, Gaipa G, Rossi V, Bugarin C, et al. Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4+CD25+GITR+Foxp3+CD62L+ functional regulatory T-cells in patients with graft-versus-host disease. Transplantation. 2007;84:31-9.
  5. Data on file, Therakos, Inc.
  6. Gatza E, Rogers CE, Clouthier SG, Lowler KP, Tawara I, Liu C, et al.  Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood. 2008;112:1515-21.
  7. Gjerdrum LM, Woetmann A, Odum N, Burton CM, Rossen K, Skovgaard GL, et al. FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. Leukemia. 2007;21(12):2512-2518.
  8. Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, et al.  Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med. 2007;204:105-15.
  9. Joffre O, van Meerwijk JP. CD4(+)CD25(+) regulatory T lymphocytes in bone marrow transplantation. Semin Immunol. 2006;18(2):128-135.
  10. Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol. 2007;178:7849-58.
  11. Lamioni A, Carsetti R, Legato A, Landolfo A, Isacchi G, Emma F, Bottazzo GF, Dello Strologo L. Induction of regulatory T cells after prophylactic treatment with photopheresis in renal transplant recipients. Transplantation. 2007;83:1393-6.
  12. Lamioni A, Carsetti R, Legato A, Landolfo A, Isacchi G, Emma F, et al. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation. 2005;79:846-50.
  13. Maeda A, Schwarz A, Kernebeck K, Gross N, Aragane Y, Peritt D, et al. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol. 2005;174:5968–76.
  14. Maeda A, Schwartz A, Bullinger A, Morita A, Peritt D, Schwartz T. Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity via two mechanisms: generation of IL-10 and induction of regulatory T cells. J Immunol. 2008;181:5956-5962.
  15. Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med. 2007;13(3):108-116.
  16. Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N.Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med. 2000;191:423-34.
  17. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003;3(3):199-210.

 

 
 

Important Safety Information

Indications

Methoxsalen Sterile Solution is indicated for extracorporeal administration with the THERAKOS UVAR XTS® or THERAKOS CELLEX® Photopheresis System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that is unresponsive to other forms of treatment.

Methoxsalen is not appropriate for patients who have had a reaction to psoralen compounds, patients who have had a light sensitive disease, or patients with an absence of one or both lenses of the eye.

THERAKOS Photopheresis is not appropriate for patients who cannot tolerate blood volume changes or patients with blood clotting disorders. See Important Safety Information for additional details.

 
 
 

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