Effects of interferon-beta on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-beta treatment in patients with multiple sclerosis.
Interferon-beta (IFN-beta) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-beta on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-beta in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-beta, and in vivo in whole blood samples of 32 untreated and 24 IFN-beta treated MS patients, including 13 patients longitudinal. IFN-beta treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-beta treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-beta (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-beta upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-beta in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-beta treatment at early timepoints during IFN-beta therapy.
Wiesemann
Elke
E
Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Deb
Milani
M
Trebst
Corinna
C
Hemmer
Bernhard
B
Stangel
Martin
M
Windhagen
Anja
A
D000328:Adult; D000906:Antibodies / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D016899:Interferon-beta / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019013:CD40 Antigens; C497964:CD86 protein, human; D007155:Immunologic Factors; D036341:Intercellular Signaling Peptides and Proteins; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050794:STAT1 Transcription Factor; D016899:Interferon-beta