main topic Wien Med Wochenschr (2015) 165:23–27 DOI 10.1007/s10354-014-0313-x
Blockade of co-stimulation in chronic inflammatory diseases Clemens Scheinecker
Received: 11 April 2014 / Accepted: 2 September 2014 / Published online: 1 October 2014 © Springer-Verlag Wien 2014
Summary Costimulatory molecules are key elements in T cell activation. Therapeutic inhibition of costimulatory pathways have been recognized as valid therapeutic strategies in the treatment of various inflammatory diseases. This article will describe their mechanisms of action and will summarize the results from clinical trials in the field of rheumatologic diseases. Keywords Costimulatory molecules · T cell activation · Antigen presenting cell · Rheumatoid arthritis
Die Blockade der Kostimulation in chronisch entzündlichen Erkrankungen Zusammenfassung Kostimulatorische Moleküle sind Schlüsselelemente in der Aktivierung von T Zellen. Die Blockierung der Kostimulation stellt eine wirksame Strategie in der Therapie verschiedener entzündlicher Erkrankungen dar. Dieser Artikel beschreibt ihren Wirkmechanismus und bietet einen Überblick über die Ergebnisse der klinischen Studien im Gebiet der Rheumatologie. Schlüsselwörter Kostimulatorische Moleküle · T Zell Aktivierung · Antigen präsentierende Zellen · Rheumatoide Arthritis
Costimulatory molecules are key elements in T cell activation. Therapeutic inhibition of costimulatory pathways have been recognized as valid therapeutic strategies in
C. Scheinecker, MD () Division of Rheumatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria e-mail: [email protected]
13
the treatment of various inflammatory diseases. This article will describe their mechanisms of action and will summarize the results from clinical trials in the field of rheumatologic diseases. Activated T cells are thought to play a prominent role in chronic inflammatory (auto)immune diseases like for example rheumatoid arthritis (RA) [1] due to their capacity to activate monocytes, macrophages, synovial fibroblasts and B cells [2, 3]. T cell activation in general requires at least two signals: the first signal is the cognate engagement of the antigenspecific T cell receptor (TCR) with peptide antigens that are presented by Major Histocompatibility Complex class II (MHC II) molecules on the surface of antigen-presenting cells (APC). The second signal is provided by the interaction of CD28 on T cells with costimulatory molecules CD80 (B7-1) and CD86 (B7-2) on APC [4, 5]. CD86 is constitutively expressed on most APC such as monocytes/macrophages, dendritic cells, and B cells whereas CD80 is rapidly upregulated upon activation. The constitutive expression of CD86 has led to the assumption that CD86 is the more important costimulatory molecule and similar conclusions have been made from experiments in knock-out mice [6]. CD28 is constitutively expressed on T cells. CD28 signaling lowers the threshold for T cell activation by reducing the number of TCRs that need to be engaged for the initiation of T cell activation [7]. CD28 also promotes T cell survival and sensitizes activated T cells for the effect of interleukin-2 (IL-2) (reviewed in [8]). In contrast to CD28, T cells start to express endogenous cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) on the cell surface upon activation. CTLA-4 also binds to costimulatory molecules, but in contrast to CD28, delivers anti-proliferative signals that downregulate T-cell activation [9–11]. CTLA-4 reduces the production of IL-2 and the expression of IL-2 receptor. In vivo, CTLA-4 blockade triggers immune responses against tumors and
Blockade of co-stimulation in chronic inflammatory diseases
23
main topic
exacerbates autoimmune reaction. CTLA-4−/− mice that lack controlled costimulation develop fatal lymphoproliferative disorders [12]. The B7-1/B7-2-CD28/CTLA-4 pathway is currently still the best characterized T-cell costimulatory pathway. Additional costimulatory pathways have recently been described. One involves the CD28 family member ICOS which interacts with ICOS ligand (ICOSL). ICOS expression is upregulated on activated T cells which suggests that it is involved in the regulation of activated T cells. In contrast to CD28, ICOS expression is not restricted to hematopoietic cells. ICOSL production seems to be regulated by inflammatory signals in peripheral sites [13]. A second costimulatory pathway involves the PD-1 receptor, which interacts with the B7 family members PD-L1 and PD-L2. Other B7 homologues are B7-H3 and the butyrophilin (BTN) family which is related to the B7s and is located in the MHC locus on human chromosome 6 (reviewed in [8]). In the absence of costimulatory signal 2, T cells fail to respond effectively and are rendered anergic. The induction of an anergic state is believed to represent one mechanism of tolerance induction. The 2-signal model therefore serves to explain the capacity of the immune system to discriminate between self and non-self. Abatacept (CTLA-4Ig) is the first biological compound that primarily aims to modulate T cell activation in chronic inflammatory diseases such as RA. Abatacept represents a soluble, recombinant, fusion protein, comprising the extracellular domain of human CTLA-4 and the Fc portion of human IgG1, which has been modified to prevent complement fixation. Abatacept possesses up to 100 fold higher affinity to CD80 and CD86 when compared with CD28. Due to its competitive binding to CD80/CD86 abatacept prevents the activation of T cells. Besides the inhibition of T cell activation binding of abatacept to CD80/CD86 might also affect APC activation and function. In line with this hypothesis our own group has recently been able to show that treatment of RA patients with abatacept increased proportions of peripheral blood CD14+ monocytes and diminished their expression of adhesion molecules. In addition abatacept reduced adhesion and transendothelial migratory capacity of isolated monocytes in vitro. These results were strengthened by similar in vitro observations with CD14+ monocytes from healthy controls suggesting that abatacept treatment exerts important effects beyond the inhibition of T cell activation [14]. CTLA-4Ig has been shown to affect a variety of T cell dependent animal models of autoimmune diseases, such as experimental autoimmune encephalomyelitis, collagen-induced arthritis (CIA), and diabetes mellitus [15, 16]. In a CIA model in rats CTLA-4-Ig treatment before immunization was found to prevent clinical and histological manifestations of the disease and reduced anti-bovine type II collagen antibody titers [15]. Similar observations have been made in the CIA mouse model, where treatment with CTLA-4Ig before immunization prevented the development of clinical signs of arthritis
and the delayed treatment after disease onset still ameliorated the disease. Interestingly neither anti-CD80 nor anti-CD86 antibodies had any effect when given alone, but reduced incidence and clinical scores when given together [17]. As for humans, the inhibition of the T cell activation has been shown to be an effective mechanism in the treatment of RA patients [18–21]. In a 6-month randomized, double-blind, placebo-controlled study Kremer et al. treated patients, who had failed a therapy with methotrexate (MTX), with 10 mg of abatacept per kilogram intravenous (i.v.). Patients receiving abatacept were more likely to achieve an ACR 20 response rate (as well as ACR 50 and ACR 70 response rates) than patients who received placebo (60 % vs 35 %, p
Blockade of co-stimulation in chronic inflammatory diseases Clemens Scheinecker
Received: 11 April 2014 / Accepted: 2 September 2014 / Published online: 1 October 2014 © Springer-Verlag Wien 2014
Summary Costimulatory molecules are key elements in T cell activation. Therapeutic inhibition of costimulatory pathways have been recognized as valid therapeutic strategies in the treatment of various inflammatory diseases. This article will describe their mechanisms of action and will summarize the results from clinical trials in the field of rheumatologic diseases. Keywords Costimulatory molecules · T cell activation · Antigen presenting cell · Rheumatoid arthritis
Die Blockade der Kostimulation in chronisch entzündlichen Erkrankungen Zusammenfassung Kostimulatorische Moleküle sind Schlüsselelemente in der Aktivierung von T Zellen. Die Blockierung der Kostimulation stellt eine wirksame Strategie in der Therapie verschiedener entzündlicher Erkrankungen dar. Dieser Artikel beschreibt ihren Wirkmechanismus und bietet einen Überblick über die Ergebnisse der klinischen Studien im Gebiet der Rheumatologie. Schlüsselwörter Kostimulatorische Moleküle · T Zell Aktivierung · Antigen präsentierende Zellen · Rheumatoide Arthritis
Costimulatory molecules are key elements in T cell activation. Therapeutic inhibition of costimulatory pathways have been recognized as valid therapeutic strategies in
C. Scheinecker, MD () Division of Rheumatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria e-mail: [email protected]
13
the treatment of various inflammatory diseases. This article will describe their mechanisms of action and will summarize the results from clinical trials in the field of rheumatologic diseases. Activated T cells are thought to play a prominent role in chronic inflammatory (auto)immune diseases like for example rheumatoid arthritis (RA) [1] due to their capacity to activate monocytes, macrophages, synovial fibroblasts and B cells [2, 3]. T cell activation in general requires at least two signals: the first signal is the cognate engagement of the antigenspecific T cell receptor (TCR) with peptide antigens that are presented by Major Histocompatibility Complex class II (MHC II) molecules on the surface of antigen-presenting cells (APC). The second signal is provided by the interaction of CD28 on T cells with costimulatory molecules CD80 (B7-1) and CD86 (B7-2) on APC [4, 5]. CD86 is constitutively expressed on most APC such as monocytes/macrophages, dendritic cells, and B cells whereas CD80 is rapidly upregulated upon activation. The constitutive expression of CD86 has led to the assumption that CD86 is the more important costimulatory molecule and similar conclusions have been made from experiments in knock-out mice [6]. CD28 is constitutively expressed on T cells. CD28 signaling lowers the threshold for T cell activation by reducing the number of TCRs that need to be engaged for the initiation of T cell activation [7]. CD28 also promotes T cell survival and sensitizes activated T cells for the effect of interleukin-2 (IL-2) (reviewed in [8]). In contrast to CD28, T cells start to express endogenous cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) on the cell surface upon activation. CTLA-4 also binds to costimulatory molecules, but in contrast to CD28, delivers anti-proliferative signals that downregulate T-cell activation [9–11]. CTLA-4 reduces the production of IL-2 and the expression of IL-2 receptor. In vivo, CTLA-4 blockade triggers immune responses against tumors and
Blockade of co-stimulation in chronic inflammatory diseases
23
main topic
exacerbates autoimmune reaction. CTLA-4−/− mice that lack controlled costimulation develop fatal lymphoproliferative disorders [12]. The B7-1/B7-2-CD28/CTLA-4 pathway is currently still the best characterized T-cell costimulatory pathway. Additional costimulatory pathways have recently been described. One involves the CD28 family member ICOS which interacts with ICOS ligand (ICOSL). ICOS expression is upregulated on activated T cells which suggests that it is involved in the regulation of activated T cells. In contrast to CD28, ICOS expression is not restricted to hematopoietic cells. ICOSL production seems to be regulated by inflammatory signals in peripheral sites [13]. A second costimulatory pathway involves the PD-1 receptor, which interacts with the B7 family members PD-L1 and PD-L2. Other B7 homologues are B7-H3 and the butyrophilin (BTN) family which is related to the B7s and is located in the MHC locus on human chromosome 6 (reviewed in [8]). In the absence of costimulatory signal 2, T cells fail to respond effectively and are rendered anergic. The induction of an anergic state is believed to represent one mechanism of tolerance induction. The 2-signal model therefore serves to explain the capacity of the immune system to discriminate between self and non-self. Abatacept (CTLA-4Ig) is the first biological compound that primarily aims to modulate T cell activation in chronic inflammatory diseases such as RA. Abatacept represents a soluble, recombinant, fusion protein, comprising the extracellular domain of human CTLA-4 and the Fc portion of human IgG1, which has been modified to prevent complement fixation. Abatacept possesses up to 100 fold higher affinity to CD80 and CD86 when compared with CD28. Due to its competitive binding to CD80/CD86 abatacept prevents the activation of T cells. Besides the inhibition of T cell activation binding of abatacept to CD80/CD86 might also affect APC activation and function. In line with this hypothesis our own group has recently been able to show that treatment of RA patients with abatacept increased proportions of peripheral blood CD14+ monocytes and diminished their expression of adhesion molecules. In addition abatacept reduced adhesion and transendothelial migratory capacity of isolated monocytes in vitro. These results were strengthened by similar in vitro observations with CD14+ monocytes from healthy controls suggesting that abatacept treatment exerts important effects beyond the inhibition of T cell activation [14]. CTLA-4Ig has been shown to affect a variety of T cell dependent animal models of autoimmune diseases, such as experimental autoimmune encephalomyelitis, collagen-induced arthritis (CIA), and diabetes mellitus [15, 16]. In a CIA model in rats CTLA-4-Ig treatment before immunization was found to prevent clinical and histological manifestations of the disease and reduced anti-bovine type II collagen antibody titers [15]. Similar observations have been made in the CIA mouse model, where treatment with CTLA-4Ig before immunization prevented the development of clinical signs of arthritis
and the delayed treatment after disease onset still ameliorated the disease. Interestingly neither anti-CD80 nor anti-CD86 antibodies had any effect when given alone, but reduced incidence and clinical scores when given together [17]. As for humans, the inhibition of the T cell activation has been shown to be an effective mechanism in the treatment of RA patients [18–21]. In a 6-month randomized, double-blind, placebo-controlled study Kremer et al. treated patients, who had failed a therapy with methotrexate (MTX), with 10 mg of abatacept per kilogram intravenous (i.v.). Patients receiving abatacept were more likely to achieve an ACR 20 response rate (as well as ACR 50 and ACR 70 response rates) than patients who received placebo (60 % vs 35 %, p
