Donor T Cell Activation Initiates Small Bowel Allograft Rejection Through an IFN-γ-Inducible Protein-10-Dependent Mechanism

Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear. In the present study, we determined the kinetics of RCMV-accelerated TVS in a rat heart transplant model. Acute RCMV infection enhances the development of TVS in rat heart allografts, and this process is initiated between 21 and 24 days posttransplantation. The virus is consistently detected in the heart grafts from day 7 until day 35 posttransplantation but is rarely found at the time of graft rejection (day 45 posttransplantation). Grafts from RCMV-infected recipients had upregulation of chemokine expression compared to uninfected controls, and the timing of this increased expression paralleled that of RCMV-accelerated neointimal formation. In addition, graft vessels from RCMV-infected grafts demonstrate the increased infiltration of T cells and macrophages during periods of highest chemokine expression. These results suggest that CMV-induced acceleration of TVS involves the increased graft vascular infiltration of inflammatory cells through enhanced chemokine expression.With the escalation in the number of immunosuppressed patients undergoing immunosuppressive therapy following solid organ or bone marrow transplantation, human cytomegalovirus (HCMV) disease has now become a major clinical problem. While the majority of HCMV infections result in subclinical disease in healthy individuals, HCMV is a significant pathogen in immunocompromised patients (1,3,4,9,26,33,34,50,51,56). Primary HCMV infection is followed by lifelong persistence of the virus in a latent state, and reactivation of the latent virus is considered to be the major source of virus in these immunocompromised individuals. HCMV has been linked to the development of atherosclerosis, arterial restenosis following angioplasty, and solid organ transplant vascular sclerosis (TVS) (26)(27)(28)47). HCMV infection doubles the 5-and 3-year rates of graft failure due to accelerated TVS in cardiac and liver transplant patients, respectively (15; L. W. Miller, Editorial, J. Heart Lung Transplant. 11:S1-S4, 1992). The observation that HCMV infects many of the cell types involved in vascular disease, including monocyte-derived macrophages, endothelial cells, and smooth muscle cells (SMC), suggests that HCMV may play a role in these disease processes. Because of the similarities between the CMV-speciesspecific viruses, animal models provide an ideal tool to study the association between CMV and TVS.The most compelling evidence that herpesviruses play a role in vascular disease comes from studies in animal models. Using a rat CMV (RCMV) solid organ transplant model, researchers have demonstrated, in light of the RCMV-associated acceleration of TVS, an association of herpesvirus ...

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“…In addition, recipient mice lacking the chemokine receptor for IP-10 failed to develop chronic rejection (12,13,29,57). As shown in Fig.…”

Section: ]) Little To No Intimal-and Medial-vessel Cd4mentioning

confidence: 75%

Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants

Streblow¹,

Kreklywich²,

Yin

et al. 2003

J Virol

108

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“…Supporting this hypothesis, CXCR3-deficient mice were protected from heart allograft transplant rejection and autoimmune type 1 diabetes mellitus in murine models (19,23). Likewise, using CXCL10-deficient mice and inhibitory monoclonal antibodies, CXCL10 was shown to play a similar role in these same models (8,22) as well as small bowel allograft rejection (48,49) and the host response to Toxoplasma gondii and murine hepatitis virus (13,24,25). Together, these data support a critical role for both CXCR3 and its ligands in T-cell-mediated inflammation.…”

Section: And Cd8mentioning

confidence: 77%

CXCR3 Requires Tyrosine Sulfation for Ligand Binding and a Second Extracellular Loop Arginine Residue for Ligand-Induced Chemotaxis

Colvin

Campanella

Manice

et al. 2006

Molecular and Cellular Biology

Self Cite

116

119

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CXCR3 is a G-protein-coupled seven-transmembrane domain chemokine receptor that plays an important role in effector T-cell and NK cell trafficking. Three gamma interferon-inducible chemokines activate CXCR3: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Here, we identify extracellular domains of CXCR3 that are required for ligand binding and activation. We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands. We also found that the proximal 16 amino acid residues of the N terminus are required for CXCL10 and CXCL11 binding and activation but not CXCL9 activation. In addition, we found that residue R216 in the second extracellular loop is required for CXCR3-mediated chemotaxis and calcium mobilization but is not required for ligand binding or ligand-induced CXCR3 internalization. Finally, charged residues in the extracellular loops contribute to the receptor-ligand interaction. These findings demonstrate that chemokine activation of CXCR3 involves both high-affinity ligand-binding interactions with negatively charged residues in the extracellular domains of CXCR3 and a lower-affinity receptor-activating interaction in the second extracellular loop. This lower-affinity interaction is necessary to induce chemotaxis but not ligand-induced CXCR3 internalization, further suggesting that different domains of CXCR3 mediate distinct functions.Chemokines, or chemoattractant cytokines, are a family of small (8-to 10-kDa) secreted proteins that play an important role in the recruitment and activation of leukocytes (29). Approximately 50 chemokines have been described, and these chemokines interact with some redundancy with 20 G-proteincoupled chemokine receptors. The chemokine system, with its ability to control the migration of leukocytes, plays a critical role in both innate and adaptive immunity.CXCR3 is a chemokine receptor that is expressed on the surface of a number of cell types, including activated CD4 ϩ and CD8 ϩ T cells, NK and NK-T cells, plasmacytoid dendritic cells, and some B cells (26,27,38,45). CXCR3 is activated by three related chemokines: CXCL9, CXCL10, and CXCL11 (9,26,27,38,45). Each of these ligands is induced by gamma interferon and is produced in Th1-type immune responses (9, 14, 31). CXCR3 has been localized to infiltrating effector T cells in a wide variety of human inflammatory diseases, including atherosclerosis (32), rheumatoid arthritis (38), multiple sclerosis (3, 43), heart and lung transplant rejection (1, 22, 50), and psoriasis (17). The CXCR3 ligands have similarly been identified in these same lesions (1,17,20,32,36), leading to the hypothesis that this receptor-ligand system plays an important role in the recruitment of effector T cells into these lesions, resulting in T-cell-mediated inflammation. Supporting this hypothesis, CXCR3-deficient mice were protected from heart allograft transplant rejection and autoimmune type 1 diabetes mellitus in murine models (19,23). Likewise, using CXCL10-deficient mice and inhi...

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“…Although CXCL10 may not directly influence T cell responses directed at controlling viral replication, it remains possible that CXCL10 may enhance antiviral functions by infiltrating NK cells as we have previously shown increased IFN-␥ production by NK cells following infection of RAG1 Ϫ/Ϫ mice with MHV-CXCL10 (21). Additional support for CXCL10 in activating NK cells is derived from models of allograft rejection as well as examining lymphocyte responses following infection of mice with an adenovirus engineered to express CXCL10 (63,64). Therefore, it is possible that the dramatic reduction in viral titers within the livers of MHV-CXCL10-infected mice correlates with enhanced NK cell activation.…”

Section: Discussionmentioning

confidence: 99%

Expression of CXC Chemokine Ligand 10 from the Mouse Hepatitis Virus Genome Results in Protection from Viral-Induced Neurological and Liver Disease

Walsh

Edwards

Romero

et al. 2007

The Journal of Immunology

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Using the recombinant murine coronavirus mouse hepatitis virus (MHV) expressing the T cell-chemoattractant CXCL10 (MHV-CXCL10), we demonstrate a potent antiviral role for CXCL10 in host defense. Instillation of MHV-CXCL10 into the CNS of CXCL10-deficient (CXCL10−/−) mice resulted in viral infection and replication in both brain and liver. Expression of virally encoded CXCL10 within the brain protected mice from death and correlated with increased infiltration of T lymphocytes, enhanced IFN-γ secretion, and accelerated viral clearance when compared with mice infected with an isogenic control virus, MHV. Similarly, viral clearance from the livers of MHV-CXCL10-infected mice was accelerated in comparison to MHV-infected mice, yet was independent of enhanced infiltration of T lymphocytes and NK cells. Moreover, CXCL10−/− mice infected with MHV-CXCL10 were protected from severe hepatitis as evidenced by reduced pathology and serum alanine aminotransferase levels compared with MHV-infected mice. CXCL10-mediated protection within the liver was not dependent on CXC-chemokine receptor 2 (CXCR2) signaling as anti-CXCR2 treatment of MHV-CXCL10-infected mice did not modulate viral clearance or liver pathology. In contrast, treatment of MHV-CXCL10-infected CXCL10−/− mice with anti-CXCL10 Ab resulted in increased clinical disease correlating with enhanced viral recovery from the brain and liver as well as increased serum alanine aminotransferase levels. These studies highlight that CXCL10 expression promotes protection from coronavirus-induced neurological and liver disease.

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Donor T Cell Activation Initiates Small Bowel Allograft Rejection Through an IFN-γ-Inducible Protein-10-Dependent Mechanism

Cited by 57 publications

References 45 publications

Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants

Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants

CXCR3 Requires Tyrosine Sulfation for Ligand Binding and a Second Extracellular Loop Arginine Residue for Ligand-Induced Chemotaxis

Expression of CXC Chemokine Ligand 10 from the Mouse Hepatitis Virus Genome Results in Protection from Viral-Induced Neurological and Liver Disease

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