The Experts below are selected from a list of 18000 Experts worldwide ranked by ideXlab platform
Wayne A Marasco - One of the best experts on this subject based on the ideXlab platform.
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anti CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft humanized mouse model
OncoImmunology, 2016Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Eric C Peterson, Calum Goudie, Joyce F Liu, Wayne A MarascoAbstract:ABSTRACTRecent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The Chemokine Receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+ Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for their in vitro activity and in vivo capacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blocked in vitro chemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in their in vivo mode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice r...
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anti CCR4 antibody enhances anti tumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft animal model vac12p 1121
Journal of Immunology, 2015Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Wayne A MarascoAbstract:Recent experimental and clinical data demonstrate that regulatory T cells (Tregs) are recruited to the tumor site where they can suppress tumor-specific immunity. Increasing evidence indicates that Treg recruitment to the tumor is mediated by the production of Chemokine CCL22, a ligand of Chemokine Receptor CCR4, by tumor cells and tumor resident macrophages. Therefore, blocking Treg migration and function through CCL22/CCR4 axis may have therapeutic value in cancer treatment. With a mouse model bearing CCL22-secreting ovarian xenograft and tumor-specific T cells, we assessed the therapeutic effect of human anti-CCR4 antibody mAb2-3 to block or modulate immunological axes involved in tumor immune evasion. CCR4 expression was demonstrated at a high level on functional CD4 + CD25 + Tregs and T cell proliferation was restored by removal of CCR4 + Tregs in vitro . In vivo examinations showed isotyping of mAb2-3 had marked effects on its mode of action: mAb2-3 IgG1 results in Treg depletion whereas IgG4 blocks in vivo chemotactic migration to CCL22-secreting ovarian cancer (OVC) cells without Treg depletion. The mAb2-3-treated mice bearing OVC xenograft and tumor-primed T cells showed the ability to inhibit Treg recruitment and resulted in potent anti-tumor immunity. The results revealed that depletion of Tregs and blockade of Treg recruitment through mAb2-3 IgG1 and IgG4, respectively, could reverse Treg suppression and improve cellular immunity against tumors.
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abstract 4754 a humanized high affinity anti CCR4 antibody for immunotherapy of cutaneous t cell lymphoma and characterization on t cell function
Cancer Research, 2013Co-Authors: Dekuan Chang, Quan Zhu, Thomas S. Kupper, Thomas Han, Rachael A Clark, Wayne A MarascoAbstract:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of Chemokine Receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, a humanized and affinity optimized anti-CCR4 monoclonal antibody (mAb), mAb2-3, was evaluated. In vitro mechanism studies demonstrated that the potent in vivo anti-tumor effects of this humanized anti-CCR4 mAb could be attributed to antibody dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP). In a mouse CTCL tumor model, anti-CCR4 mAb exhibited an antitumor effect by mediating cellular cytotoxicity through CDC and ADCC via FcγRIIIa expressed murine neutrophils and human nature killer (NK) cells. Moreover, this anti-CCR4 mAb also effectively inhibits chemotaxis of CD4+CD25high Tregs via CCL22 and abrogates Treg suppression activity in vitro by restoring the proliferation of CD4+CD25− effector T cells (Teffs). Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action on immunity may provide a novel immunotherapy for CTCL and other solid tumors. Citation Format: DeKuan Chang, Thomas Han, Rachael A. Clark, Quan Zhu, Thomas S. Kupper, Wayne A. Marasco. A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2013-4754
Dekuan Chang - One of the best experts on this subject based on the ideXlab platform.
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anti CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft humanized mouse model
OncoImmunology, 2016Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Eric C Peterson, Calum Goudie, Joyce F Liu, Wayne A MarascoAbstract:ABSTRACTRecent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The Chemokine Receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+ Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for their in vitro activity and in vivo capacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blocked in vitro chemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in their in vivo mode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice r...
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anti CCR4 antibody enhances anti tumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft animal model vac12p 1121
Journal of Immunology, 2015Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Wayne A MarascoAbstract:Recent experimental and clinical data demonstrate that regulatory T cells (Tregs) are recruited to the tumor site where they can suppress tumor-specific immunity. Increasing evidence indicates that Treg recruitment to the tumor is mediated by the production of Chemokine CCL22, a ligand of Chemokine Receptor CCR4, by tumor cells and tumor resident macrophages. Therefore, blocking Treg migration and function through CCL22/CCR4 axis may have therapeutic value in cancer treatment. With a mouse model bearing CCL22-secreting ovarian xenograft and tumor-specific T cells, we assessed the therapeutic effect of human anti-CCR4 antibody mAb2-3 to block or modulate immunological axes involved in tumor immune evasion. CCR4 expression was demonstrated at a high level on functional CD4 + CD25 + Tregs and T cell proliferation was restored by removal of CCR4 + Tregs in vitro . In vivo examinations showed isotyping of mAb2-3 had marked effects on its mode of action: mAb2-3 IgG1 results in Treg depletion whereas IgG4 blocks in vivo chemotactic migration to CCL22-secreting ovarian cancer (OVC) cells without Treg depletion. The mAb2-3-treated mice bearing OVC xenograft and tumor-primed T cells showed the ability to inhibit Treg recruitment and resulted in potent anti-tumor immunity. The results revealed that depletion of Tregs and blockade of Treg recruitment through mAb2-3 IgG1 and IgG4, respectively, could reverse Treg suppression and improve cellular immunity against tumors.
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abstract 4754 a humanized high affinity anti CCR4 antibody for immunotherapy of cutaneous t cell lymphoma and characterization on t cell function
Cancer Research, 2013Co-Authors: Dekuan Chang, Quan Zhu, Thomas S. Kupper, Thomas Han, Rachael A Clark, Wayne A MarascoAbstract:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of Chemokine Receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, a humanized and affinity optimized anti-CCR4 monoclonal antibody (mAb), mAb2-3, was evaluated. In vitro mechanism studies demonstrated that the potent in vivo anti-tumor effects of this humanized anti-CCR4 mAb could be attributed to antibody dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP). In a mouse CTCL tumor model, anti-CCR4 mAb exhibited an antitumor effect by mediating cellular cytotoxicity through CDC and ADCC via FcγRIIIa expressed murine neutrophils and human nature killer (NK) cells. Moreover, this anti-CCR4 mAb also effectively inhibits chemotaxis of CD4+CD25high Tregs via CCL22 and abrogates Treg suppression activity in vitro by restoring the proliferation of CD4+CD25− effector T cells (Teffs). Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action on immunity may provide a novel immunotherapy for CTCL and other solid tumors. Citation Format: DeKuan Chang, Thomas Han, Rachael A. Clark, Quan Zhu, Thomas S. Kupper, Wayne A. Marasco. A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2013-4754
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humanization of an anti CCR4 antibody that kills cutaneous t cell lymphoma cells and abrogates suppression by t regulatory cells
Molecular Cancer Therapeutics, 2012Co-Authors: Dekuan Chang, Robert C. Fuhlbrigge, Jianhua Sui, Shusheng Geng, Asli Muvaffak, Mei Bai, Anuradha Yammanuru, Luke Hubbard, Jared Sheehan, James J CampbellAbstract:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of Chemokine Receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, we conducted humanization and affinity optimization of a murine anti-CCR4 monoclonal antibody (mAb), mAb1567, that recognizes both the N-terminal and extracellular domains of CCR4 with high affinity and inhibits chemotaxis of CCR4(+) CTCL cells. In a mouse CTCL tumor model, mAb1567 exhibited a potent antitumor effect and in vitro mechanistic studies showed that both complement-dependent cytotoxicity (CDC) and neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) likely mediated this effect. mAb1567 also exerts human NK cell-mediated ADCC activity in vitro. Moreover, mAb1567 also effectively inhibits chemotaxis of CD4(+)CD25(high) Tregs via CCL22 and abrogates Treg suppression activity in vitro. An affinity-optimized variant of humanized mAb1567, mAb2-3, was selected for further preclinical development based on its higher binding affinity and more potent ADCC and CDC activities. Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action may provide a novel immunotherapy for CTCL and other solid tumors.
Quan Zhu - One of the best experts on this subject based on the ideXlab platform.
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anti CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft humanized mouse model
OncoImmunology, 2016Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Eric C Peterson, Calum Goudie, Joyce F Liu, Wayne A MarascoAbstract:ABSTRACTRecent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The Chemokine Receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+ Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for their in vitro activity and in vivo capacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blocked in vitro chemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in their in vivo mode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice r...
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anti CCR4 antibody enhances anti tumor immunity by modulating tumor infiltrating tregs in an ovarian cancer xenograft animal model vac12p 1121
Journal of Immunology, 2015Co-Authors: Dekuan Chang, Jiusong Sun, Quan Zhu, Ronny Drapkin, Ursula A Matulonis, Wayne A MarascoAbstract:Recent experimental and clinical data demonstrate that regulatory T cells (Tregs) are recruited to the tumor site where they can suppress tumor-specific immunity. Increasing evidence indicates that Treg recruitment to the tumor is mediated by the production of Chemokine CCL22, a ligand of Chemokine Receptor CCR4, by tumor cells and tumor resident macrophages. Therefore, blocking Treg migration and function through CCL22/CCR4 axis may have therapeutic value in cancer treatment. With a mouse model bearing CCL22-secreting ovarian xenograft and tumor-specific T cells, we assessed the therapeutic effect of human anti-CCR4 antibody mAb2-3 to block or modulate immunological axes involved in tumor immune evasion. CCR4 expression was demonstrated at a high level on functional CD4 + CD25 + Tregs and T cell proliferation was restored by removal of CCR4 + Tregs in vitro . In vivo examinations showed isotyping of mAb2-3 had marked effects on its mode of action: mAb2-3 IgG1 results in Treg depletion whereas IgG4 blocks in vivo chemotactic migration to CCL22-secreting ovarian cancer (OVC) cells without Treg depletion. The mAb2-3-treated mice bearing OVC xenograft and tumor-primed T cells showed the ability to inhibit Treg recruitment and resulted in potent anti-tumor immunity. The results revealed that depletion of Tregs and blockade of Treg recruitment through mAb2-3 IgG1 and IgG4, respectively, could reverse Treg suppression and improve cellular immunity against tumors.
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abstract 4754 a humanized high affinity anti CCR4 antibody for immunotherapy of cutaneous t cell lymphoma and characterization on t cell function
Cancer Research, 2013Co-Authors: Dekuan Chang, Quan Zhu, Thomas S. Kupper, Thomas Han, Rachael A Clark, Wayne A MarascoAbstract:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of Chemokine Receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, a humanized and affinity optimized anti-CCR4 monoclonal antibody (mAb), mAb2-3, was evaluated. In vitro mechanism studies demonstrated that the potent in vivo anti-tumor effects of this humanized anti-CCR4 mAb could be attributed to antibody dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP). In a mouse CTCL tumor model, anti-CCR4 mAb exhibited an antitumor effect by mediating cellular cytotoxicity through CDC and ADCC via FcγRIIIa expressed murine neutrophils and human nature killer (NK) cells. Moreover, this anti-CCR4 mAb also effectively inhibits chemotaxis of CD4+CD25high Tregs via CCL22 and abrogates Treg suppression activity in vitro by restoring the proliferation of CD4+CD25− effector T cells (Teffs). Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action on immunity may provide a novel immunotherapy for CTCL and other solid tumors. Citation Format: DeKuan Chang, Thomas Han, Rachael A. Clark, Quan Zhu, Thomas S. Kupper, Wayne A. Marasco. A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2013-4754
Christian Vestergaard - One of the best experts on this subject based on the ideXlab platform.
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expression of mdc ccl22 and its Receptor CCR4 in rheumatoid arthritis psoriatic arthritis and osteoarthritis
Cytokine, 2010Co-Authors: Helene Aarslev Flytlie, Christian Vestergaard, Mette Deleuran, Malene Hvid, Esther Lindgreen, Emil Kofodolsen, Eva Lykke Petersen, Anette Jorgensen, Bent DeleuranAbstract:The pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) involves an abnormal Chemokine regulation. The Chemokine Receptor CCR4 is necessary for T cell migration to the skin. We, therefore, studied if CCR4 and its ligand macrophage-derived Chemokine (MDC/CCL22) could participate in spreading the disease between skin and joints by examining RA, PsA and osteoarthritis (OA) patients. In synovial fluid from RA and PsA patients we observed a significantly higher MDC/CCL22 level compared to OA patients. Additionally, the MDC/CCL22 protein was found to be elevated in RA and PsA plasma compared to OA and healthy volunteers. Flow cytometry revealed that most CD4(+)CCR4(+) lymphocytes also co-expressed CD45RO. Neither the MDC/CCL22 level nor the expression of CCR4 correlated to CRP. Immunohistochemistry of the RA and OA synovial membrane demonstrated CCR4 to be expressed by mononuclear cells and endothelial cells. Our results show that MDC/CCL22 is present within the synovial membrane of RA and OA patients and in high amount in the synovial fluid of patients with RA and PsA. This will enable migration of CCR4 expressing memory cells supporting that MDC/CCR4 could play a role in attracting skin specific memory T cells to the joints.
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Expression of the T-helper 2-specific Chemokine Receptor CCR4 on CCR10-positive lymphocytes in atopic dermatitis skin but not in psoriasis skin.
The British journal of dermatology, 2003Co-Authors: Christian Vestergaard, Mette Deleuran, Borbala Gesser, C. Grønhøj LarsenAbstract:Summary Background Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases. AD is generally perceived as a T-helper (Th) 2-dominated disease whereas psoriasis is a Th1-dominated disease. The Chemokine cutaneous T-cell attracting Chemokine (CTACK) and its Receptor CCR10 attract skin-homing lymphocytes to inflamed skin, suggesting that CCR10+ cells in AD and psoriasis should be of Th2 and Th1 type, respectively. The Chemokine Receptor CCR4 is expressed selectively on Th2 lymphocytes and its ligand thymus and activation-regulated Chemokine (TARC) is upregulated in AD lesions, suggesting that the CCR10+ cells in AD lesions should also express CCR4. Objectives To examine the coexpression of CCR10 and CCR4 on skin-invading lymphocytes in AD and psoriasis lesions as well as the Th1/Th2 cytokine expression of the CCR10+ lymphocytes. Methods Skin biopsies from AD and psoriasis patients were double stained with antibodies against CCR10–CCR4, CCR10–CCR5, CCR10–interleukin (IL)-2 and CCR10–IL-4. Results The CCR10+ cells in AD showed a mixed IL-2/IL-4 expression pattern, and a minor proportion expressed CCR4, whereas a large proportion of the CCR4+ cells did not express CCR10. In psoriasis the CCR10+ cells only expressed IL-2, and no CCR4 expression was detected. Conclusions The CCR10+ lymphocytes invading the skin in AD and psoriasis have different Th1/Th2 profiles, as measured by both their cytokine and Chemokine Receptor expression. This suggests that the CCR10+ subpopulation of lymphocytes is made up of different Th1/Th2 subsets. However, the Th1/Th2 lymphocytes of AD and psoriasis were either CCR10+ or CCR10–, suggesting that both the Th1 and Th2 subpopulation can be subdivided further. CCR4 was found only in AD skin and on both CCR10+ and CCR10– cells, supporting the hypothesis of TARC and CTACK as being independent lymphocyte-attracting Chemokines in AD.
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a th2 Chemokine tarc produced by keratinocytes may recruit cla CCR4 lymphocytes into lesional atopic dermatitis skin
Journal of Investigative Dermatology, 2000Co-Authors: Christian Vestergaard, Borbala Gesser, Karen Bang, Hiroyuki Yoneyama, Kouji Matsushima, Christian LarsenAbstract:Atopic dermatitis is an inflammatory skin disease in which the inflammation is characterized by the influx of lymphocytes into the dermis. It is generally believed that atopic dermatitis is a Th 2 -type disease, i.e., the T lymphocytes produce interleukin-4, interleukin-5, interleukin-10, and interleukin-13, although it has become evident in recent years that the cytokine profile in the skin changes during the course of the disease towards a Th 1 -Th 2 mixed cytokine profile (interferon-γ, tumor necrosis factor α, and interleukin-2). The lymphocytes that home into the skin express cutaneous lymphocyte-associated antigen, and it has recently been shown that most of the lymphocytes in this population express the Chemokine Receptor CCR4. CCR4 is the Receptor for the CC Chemokine TARC (thymus and activation regulated Chemokine), and this Chemokine is expressed predominantly by keratinocytes in the basal layer of the epidermis of lesional atopic dermatitis skin in mice. In humans, however, it was shown to be expressed in the endothelial cells of the dermis. We have examined the peripheral blood mononuclear cells of atopic dermatitis patients for the expression of cutaneous lymphocyte-associated antigen and CCR4 and compared them with peripheral blood mononuclear cells from normal controls. We found that the proportion of CLA + CCR4 + lymphocytes is upregulated in atopic dermatitis patients. In addition we have examined skin biopsies of lesional and non-lesional skin from atopic dermatitis patients and found that the keratinocytes, but not the endothelial cells, produce TARC in the lesional but not in the nonlesional skin. To gain insight in the stimulatory mechanisms for TARC production in keratinocytes, as previously observed in mice, we cultured HaCaT cells and found that interferon-γ and tumor necrosis factor α work synergistically to induce TARC production. These observations suggest that the induction of TARC production in keratinocytes plays an important role in the late phase skin invasion by CCR4 + CLA + Th 2 -type lymphocytes in atopic dermatitis.
James J Campbell - One of the best experts on this subject based on the ideXlab platform.
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humanization of an anti CCR4 antibody that kills cutaneous t cell lymphoma cells and abrogates suppression by t regulatory cells
Molecular Cancer Therapeutics, 2012Co-Authors: Dekuan Chang, Robert C. Fuhlbrigge, Jianhua Sui, Shusheng Geng, Asli Muvaffak, Mei Bai, Anuradha Yammanuru, Luke Hubbard, Jared Sheehan, James J CampbellAbstract:Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of Chemokine Receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, we conducted humanization and affinity optimization of a murine anti-CCR4 monoclonal antibody (mAb), mAb1567, that recognizes both the N-terminal and extracellular domains of CCR4 with high affinity and inhibits chemotaxis of CCR4(+) CTCL cells. In a mouse CTCL tumor model, mAb1567 exhibited a potent antitumor effect and in vitro mechanistic studies showed that both complement-dependent cytotoxicity (CDC) and neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) likely mediated this effect. mAb1567 also exerts human NK cell-mediated ADCC activity in vitro. Moreover, mAb1567 also effectively inhibits chemotaxis of CD4(+)CD25(high) Tregs via CCL22 and abrogates Treg suppression activity in vitro. An affinity-optimized variant of humanized mAb1567, mAb2-3, was selected for further preclinical development based on its higher binding affinity and more potent ADCC and CDC activities. Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action may provide a novel immunotherapy for CTCL and other solid tumors.
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iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity
Journal of immunology (Baltimore Md. : 1950), 2007Co-Authors: Everett Meyer, James J Campbell, Marcandre Wurbel, Tracy L. Staton, Muriel Pichavant, Matthew J. Kan, Paul B. Savage, Rosemarie H. Dekruyff, Eugene C. Butcher, Dale T. UmetsuAbstract:iNKT cells are required for the induction of airway hyperreactivity (AHR), a cardinal feature of asthma, but how iNKT cells traffic to the lungs to induce AHR has not been previously studied. Using several models of asthma, we demonstrated that iNKT cells required the Chemokine Receptor CCR4 for pulmonary localization and for the induction of AHR. In both allergen-induced and glycolipid-induced models of AHR, wild-type but not CCR4−/− mice developed AHR. Furthermore, adoptive transfer of wild-type but not CCR4−/− iNKT cells reconstituted AHR in iNKT cell-deficient mice. Moreover, we specifically tracked CCR4−/− vs wild-type iNKT cells in CCR4−/−:wild-type mixed BM chimeric mice in the resting state, and when AHR was induced by protein allergen or glycolipid. Using this unique model, we showed that both iNKT cells and conventional T cells required CCR4 for competitive localization into the bronchoalveolar lavage/airways compartment. These results establish for the first time that the pulmonary localization of iNKT cells critical for the induction of AHR requires CCR4 expression by iNKT cells.
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cutting edge Chemokine Receptor CCR4 is necessary for antigen driven cutaneous accumulation of cd4 t cells under physiological conditions
Journal of Immunology, 2007Co-Authors: James J Campbell, Daniel J Oconnell, Marcandre WurbelAbstract:Dual expression of Chemokine Receptor CCR4 and E-selectin ligand is characteristic of skin-tropic CD4 T cells from blood, lymphoid organs, and the skin itself. A strong and specific correlation exists among CCR4, its ligand CCL17/TARC, and the cutaneous lymphocyte-homing process. Nevertheless, whether CCR4 function is required for skin-specific trafficking remains an open question, which we address in this study. We developed an Ag-specific, TCR-transgenic, murine CD4 T cell adoptive transfer model that induces a mixed Th1 and Th17 cutaneous response. Within the hosts, both CCR4+/+ and CCR4−/− donor CD4 T cells contribute equally well to the circulating E-selectin ligand+ pool in response to Ag. However, only CCR4+/+ donor cells accumulate efficiently within the skin. CCR4−/− cells home normally to the peritoneum, showing that they do not have a general defect in lymphocyte trafficking. We conclude that under physiological conditions, CCR4 is a nonredundant, necessary component of skin-specific lymphocyte trafficking.
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the Chemokine Receptor CCR4 in vascular recognition by cutaneous but not intestinal memory t cells
Nature, 1999Co-Authors: James J Campbell, David P. Andrew, Guttorm Haraldsen, Junliang Pan, James B Rottman, S Qin, Paul D Ponath, Roger A Warnke, Nancy RuffingAbstract:Lymphocytes that are responsible for regional (tissue-specific) immunity home from the blood to the intestines, inflamed skin or other sites through a multistep process involving recognition of vascular endothelial cells and extravasation. Chemoattractant cytokine molecules known as Chemokines regulate this lymphocyte traffic, in part by triggering arrest (stopping) of lymphocytes rolling on endothelium. Here we show that many systemic memory T cells in blood carry the Chemokine Receptor CCR4 and therefore respond to its ligands, the Chemokines TARC and MDC. These cells include essentially all skin-homing cells expressing the cutaneous lymphocyte antigen and a subset of other systemic memory lymphocytes; however, intestinal (alpha4beta7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity of venules and infiltration of many CCR4+ lymphocytes in chronically inflamed skin, but not in the gastrointestinal lamina propria. Moreover, TARC induces integrin-dependent adhesion of skin (but not intestinal) memory T cells to the cell-adhesion molecule ICAM-1, and causes their rapid arrest under physiological flow. Our results suggest that CCR4 and TARC are important in the recognition of skin vasculature by circulating T cells and in directing lymphocytes that are involved in systemic as opposed to intestinal immunity to their target tissues.