title: Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies.
abstract: Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137(+) cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin Campus Mitte, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Keeren
authors.forename: Markus
authors.initials: M
authors.lastname: Friedrich
authors.forename: Inga
authors.initials: I
authors.lastname: Gebuhr
authors.forename: Sandra
authors.initials: S
authors.lastname: Philipp
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.forename: Wolfram
authors.initials: W
authors.lastname: Sterry
authors.forename: Christine
authors.initials: C
authors.lastname: Brandt
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Gerald
authors.initials: G
authors.lastname: Grütz
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
mesh_terms: D000077944:Alefacept; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics*; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000175:diagnosis* / Q000628:therapy; D060890:B7-H1 Antigen; D049109:Cell Proliferation; D003879:Dermatologic Agents; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018960:Hyaluronan Receptors; D007167:Immunotherapy; D007962:Leukocytes / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011565:Psoriasis / Q000175:diagnosis / Q000188:drug therapy; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D003879:Dermatologic Agents; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; C543717:TOAG-1 protein, mouse; C098946:hyaluronan-mediated motility receptor; D000077944:Alefacept