Monokine induced by IFN-γ (MIG; CXC chemokine ligand (CXCL)9) is important in T lymphocyte recruitment in organ transplantation. However, it is not known whether this chemokine, in addition to its chemotactic properties, exerts any effect on T lymphocyte effector functions. For in vivo studies, we used a previously characterized murine model of chronic rejection. The recipient mice were treated with anti-MIG/CXCL9 Ab; graft-infiltrating cells were analyzed for IFN-γ production. For in vitro studies, exogenous CXCR3 ligands were added to CD4 lymphocytes in MLRs, and the proliferative responses were measured. Separate experiments quantitated the number of IFN-γ-producing cells in MLRs by ELISPOT. Neutralization of MIG/CXCL9, in the in vivo model, resulted in significant reduction in the percentage of IFN-γ-producing graft-infiltrating T lymphocytes. In vitro experiments demonstrated that 1) exogenous MIG/CXCL9 stimulated CD4 lymphocyte proliferation in a MHC class II-mismatched MLR, 2) MIG/CXCL9 also increased the number of IFN-γ-producing CD4 lymphocytes in ELISPOT, 3) neutralization of MIG/CXCL9 in MLR reduced T lymphocyte proliferation, 4) IFN-γ-inducible protein 10/CXCL10 and IFN-inducible T cell α chemoattractant/CXCL11 had similar effects on T lymphocyte proliferation, 5) MIG/CXCL9 stimulated T lymphocyte proliferation in MHC class I- and total MHC-mismatched MLRs, 6) neutralization of CXCR3 reduced MIG/CXCL9-induced T lymphocyte proliferation and the number of IFN-γ-positive spots on ELISPOT, and 7) the proliferative effects of MIG/CXCL9 were mediated via an IL-2-independent pathway and were controlled by IFN-γ. This study demonstrates that MIG/CXCL9 stimulates T lymphocyte proliferation and effector cytokine production, in addition to its chemotactic effects. This novel observation expands our current understanding of MIG/CXCL9 biology beyond that of mediating T cell trafficking.
Background-Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV).In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model. Methods and Results-B6.CH-2 bm12 strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2 ϩ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts. Conclusions-Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.
OBJECTIVES: Neonatal abstinence syndrome (NAS) is a postnatal withdrawal syndrome experienced by some infants with opioid exposure. Hospital administrative data are commonly used for research and surveillance but have not been validated for NAS. Our objectives for this study were to validate the diagnostic codes for NAS and to develop an algorithm to optimize identification. METHODS: Tennessee Medicaid claims from 2009 to 2011 (primary sample) and 2016 (secondary sample; post-International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM]) were obtained. Cases of NAS were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification code (2009-2011) 779.5 and ICD-10-CM code (2016) P96.1. Medical record review cases were then conducted by 2 physicians using a standardized algorithm, and positive predictive value (PPV) was calculated. Algorithms were developed for optimizing the identification of NAS in administrative data. RESULTS: In our primary sample of 112 029 mother-infant dyads, 950 potential NAS cases were identified from Medicaid claims data and reviewed. Among reviewed records, 863 were confirmed as having NAS (including 628 [66.1%] cases identified as NAS requiring pharmacotherapy, 224 [23.5%] as NAS not requiring pharmacotherapy, and 11 [1.2%] as iatrogenic NAS), and 87 (9.2%) did not meet clinical criteria for NAS. The PPV of the International Classification of Diseases, Ninth Revision, Clinical Modification code for NAS in clinically confirmed NAS was 91% (95% confidence interval: 88.8%-92.5%). Similarly, the PPV for the ICD-10-CM code in the secondary sample was 98.2% (95% confidence interval: 95.4%-99.2%). Algorithms using elements from the Medicaid claims and from length of stay improved PPV. CONCLUSIONS: In a large population-based cohort of Medicaid participants, hospital administrative data had a high PPV in identifying cases of clinically diagnosed NAS.
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