Lymphocyte homing and immunology of extranodal lymphoid tissues
Franco Cavalli, Harald Stein, Emanuele Zucca in Extranodal Lymphomas, 2008
The importance of PTX-inhibitable GPCRs in triggering adhesion of rolling lymphocytes in the HEV has been understood since the early 1990s.7 However, it was not until 1998 that members of the chemokine and chemokine receptor families23 were formally implicated in this role. The first breakthrough came when it was discovered that only three of the more than 40 known chemokines (including CCL21/SLC) had the unique ability to trigger rapid and robust (~30 ms) adhesion of rolling lymphocytes to ICAM-1 in vitro.17 The receptor that is present on lymphocytes, and shown to be responsible for this effect, was identified as CCR7.24,25 The second breakthrough came when in-situ hybridization studies revealed that in the mouse CCL21 was produced directly by the endothelial cells of HEV.26,27 Thus, circumstantial evidence strongly implicated CCL21/CCR7 interactions as key components of the process by which lymphocytes home to LNs and PPs from the blood.
Immunology
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
Aside from their role in leukocyte migration, chemokines are also able to direct some immune effector mechanisms. Some chemokines, particularly those that act to attract polymorphonuclear cells, are able to cause respiratory burst and degranulation, while also influencing the movement of these cells. Chemokines play a role in the activation of lymphocytes by APC, and can influence the polarization of the immune response toward antibody- or cell-based responses. Chemokines are also involved in the metastasis of cancer cells. Cancers are characterized by a distinct metastatic pattern involving the regional lymph nodes, and tissues such as bone marrow, lung, and liver. For example, it has been demonstrated that the chemokine receptor CCR7 is highly expressed in many human cancer cells, malignant tumors, and metastases. Its ligand CCL21 is expressed in organs representing the first destinations of cancer metastasis.
New Approaches for Optimizing Melanoma Vaccines
Sanjiv S. Agarwala, Vernon K. Sondak in Melanoma, 2008
Optimizing DC-T cell interactions is another strategy that is being explored to improve vaccine efficacy. It is known that ex vivo-derived DC administered intradermally do not efficiently migrate from the vaccination site to the regional lymph nodes (24,25). As direct interaction between T cells and DC in the lymph node is pivotal for the initiation of antitumor T cell responses, a failure thereof may contribute to the low clinical response rate for patients treated with DC-based immunotherapy. To improve DC-T cell interactions at the site of vaccination, the use of CCL21-SLC (Secondary Lymphoid-Tissue Chemokine) modified DC is being explored. CCL21 is a chemokine expressed in the high endothelial venules and the T cell zones of the spleen and lymph nodes. This chemokine is required for homing of CCR7+ naïve T cells and mature DC to lymphoid organs. In murine models of melanoma, transduction of tumor lysate-pulsed DC with the CCL21 gene and its expression has led to T cell stimulation at the site of vaccination, bypassing the requirement of lymph node involvement (26). Direct injection of DC expressing the CCL21 gene into an established melanoma led to an influx of tumor-specific T cells as well as a systemic antitumor immune response capable of inhibiting growth of metastatic lesions (27). In preclinical models, transduction of human monocyte–derived DC with an adenovirus expressing the CCL21 gene leads to enhanced migration of DC and T cells and priming of MART-1-specific T cell responses in vitro (28,29). A phase I trial testing CCL21 gene–modified lysate-pulsed DC in melanoma patients is pending.
CCL21/CCR7 axis regulates demyelination and vascular cognitive impairment in a mouse model for chronic cerebral hypoperfusion
Published in Neurological Research, 2023
Xuelian Tang, Cunsheng Wei, Rui Zhang, Jie You, Xuemei Chen
CCL21 is a member of the C–C chemokine family, which is associated with cell proliferation, maturation, migration, and inflammation [19]. CCL21 is expressed by lymphoid tissues, endothelial cells, as well as neurons [20,21]. CCL21 is involved in numerous human diseases including rheumatoid arthritis, viral diseases, acute coronary syndrome and cancer metastasis [22–25]. In central nervous system (CNS), the expression of CCL21 is triggered by injury, infectious and hypoperfusion [26]. Data gathered over the recent years show that CCL21, vias its receptor CCR7, plays an important role in Lyme neuroborreliosis, cerebrovascular ischemia, hematopoetic tumors, autoimmune demyelination in the CNS [27]. However, there are no reports on the influence of CCL21 on the WML induced by chronic cerebral hypoperfusion.
The Important Role of the Chemokine Axis CCR7-CCL19 and CCR7-CCL21 in the Pathophysiology of the Immuno-inflammatory Response in Dry Eye Disease
Published in Ocular Immunology and Inflammation, 2021
Ting Wang, Weihua Li, Huanhuan Cheng, Lei Zhong, Juan Deng, Shiqi Ling
Then, we studied the ligands of CCR7, CCL19 and CCL21. The mRNA levels of both CCL19 and CCL21 were upregulated, and the most obvious upregulation was observed on day 3. Furthermore, CCR7, CCL19 and CCL21 exhibited the same temporal trend as they were rapidly upregulated, reached their maximum values during the induction of DED (days 1–3), and then decreased slowly. CCR7 was detected around and in lymphatic vessels, and both CCL19 and CCL21 colocalized with CCR7 and were expressed in and around the lymphatic vessels. These findings indicated that CCR7 was expressed in mature DCs and combined with CCL19 or CCL21 to facilitate the migration of mature DCs to lymphatic vessels. The CCR7-CCL19/CCL21 chemokine axis is vital to the regulation of adaptive immunity and tolerance by affecting the migration of mature DCs from the peripheral tissue to lymphatic vessels and lymph nodes.41,42 The results of our study showed that both the CCR7-CCL21 and CCR7-CCL19 chemokine axis are important in DED.
Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL
Published in mAbs, 2021
Carlos Cuesta-Mateos, Raquel Juárez-Sánchez, Tamara Mateu-Albero, Javier Loscertales, Wim Mol, Fernando Terrón, Cecilia Muñoz-Calleja
CAP-100 can also impair positioning of tumor cells in protective niches in the LN. CAP-100 significantly delayed disease onset and reduced tumor burden reproducing results by Rehm et al. who proposed the exclusion of CCR7-deficient lymphoma cells from tumor niches as a mechanism to impair protective environment formation in LN and spleen.7 Accordingly, CCR7 levels remain high on CLL cells following their SLOs homing and it is known to guide CLL cells toward niches where accessory cells provide reciprocal crosstalk and trophic factors that can promote tumor progression.7,18,42–44 In these niches, soluble CCL19/CCL21 are also available and activate CCR7-induced survival,19,20,30 a process inhibited by CAP-100 in vitro and in vivo, especially in the LN and spleen. Moreover, CAP-100 demonstrated activity reducing the proportion of Ki67+ Granta-519 cells in LN, spleen and BM, therefore anti-proliferative activities in patients may be expected.
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