Allergic asthma is an inflammatory disease of the airways characterized by eosinophilic inflammation and airway hyper-reactivity. Cytokines and chemokines specific for Th2-type inflammation predominate in asthma and in animal models of this disease. The role of Th1-type inflammatory mediators in asthma remains controversial. IFN-γ-inducible protein 10 (IP-10; CXCL10) is an IFN-γ-inducible chemokine that preferentially attracts activated Th1 lymphocytes. IP-10 is up-regulated in the airways of asthmatics, but its function in asthma is unclear. To investigate the role of IP-10 in allergic airway disease, we examined the expression of IP-10 in a murine model of asthma and the effects of overexpression and deletion of IP-10 in this model using IP-10-transgenic and IP-10-deficient mice. Our experiments demonstrate that IP-10 is up-regulated in the lung after allergen challenge. Mice that overexpress IP-10 in the lung exhibited significantly increased airway hyperreactivity, eosinophilia, IL-4 levels, and CD8+ lymphocyte recruitment compared with wild-type controls. In addition, there was an increase in the percentage of IL-4-secreting T lymphocytes in the lungs of IP-10-transgenic mice. In contrast, mice deficient in IP-10 demonstrated the opposite results compared with wild-type controls, with a significant reduction in these measures of Th2-type allergic airway inflammation. Our results demonstrate that IP-10, a Th1-type chemokine, is up-regulated in allergic pulmonary inflammation and that this contributes to the airway hyperreactivity and Th2-type inflammation seen in this model of asthma.

Purpose: To test the hypothesis that the primary, secondary, and tertiary eigenvectors of the diffusion tensor (DT) measured with DT-MRI correspond to the fiber, sheet, and sheet normal directions, respectively, we compared DT-MRI data with the texture visible in the cut face of fresh bovine myocardium. Materials and Methods:DT-MRI and optical images obtained under identical conditions were compared objectively. Ink prints were made of the cut tissue, and the local orientations within these images were defined by analysis of local autocorrelations for regions matching DT-MRI pixels. Deviation angles between the cleavage orientations and the diffusion eigenvectors were analyzed in eight specimens sliced in three orthogonal planes. Results: Root-mean-square (RMS) angular disparity was 11°between the first eigenvectors of the DT and the fiber direction, 14°between the second eigenvector and the sheet direction, 14°between the third eigenvector and the sheet normal direction, and 15°between the tensor orientation in the imaging plane and the cleavage orientation of the cut face. Conclusion:The results support a parallel relationship between the eigenvectors of the DT and symmetry axes of the myocardial architecture. Specifically, the first, second and third eigenvectors correspond to the fiber, sheet, and sheet normal directions, respectively.

Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4 ؉ T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5 -/-(C57BL/6) recipients survived significantly longer (mean survival time, 38 ؎ 8 days) compared with those transplanted into wild-type control mice (10 ؎ 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5 -/-animals without other treatment survived >90 days. In CCR5 -/-mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-␥ was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzymelinked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection. Diabetes 51:2489 -2495, 2002 T hrough activation of the G-protein-coupled cellsurface receptor on target cells, chemokines and their receptors play a major role in the process by which leukocytes are recruited from the bloodstream into sites of inflammation, and several have been implicated in allograft rejection (1). CC chemokine receptor 5 (CCR5) is the receptor for the proinflammatory chemokines: RANTES (regulated on activation normal T-cell expressed and secreted) (CC chemokine ligand 5 [CCL5]), macrophage inflammatory protein (MIP)-1␣ (CCL3), and MIP-1␤ (CCL4) (1). Th1 cells express CCR5 and CXC chemokine receptor 3 (CXCR3) following activation, whereas activated T helper 2 (Th2) cells express CCR3, CCR4, and CCR8 (2,3). Synthesis of the chemokines MIP-1␣, MIP-1␤, and RANTES has been shown to be associated with a Th1 response (4). In vitro chemotaxis assays have shown that, whereas MIP-1␣, MIP-1␤, and RANTES were efficient chemoattractants for Th1 cells to induce a dose-dependent transmigration, Th2 cells were not attracted by these chemokines (5). In heart allografts, the early expression of some chemokines, including MIP-1␣ and MIP-1␤, subsides by day 7-9 posttransplant and is replaced by a late expression of other chemokines such as inducible protein (IP)-10 (CXCL10), monokine induced by interferon-␥ (Mig) (CXCL9) (ligands for CXCR3), and RANTES (a ligand for CCR5) (6). Met-RANTES, a CCR5 antagonist, can reduce the severity of chronic renal allograft rejection in the Lewis3 Fisher model. This effect has been attributed to blocking RANTES-induced firm adhesion of monocytes, monocyte arrest, and recruitment (7). It has recently been demonstrated that targeting CCR5 prolongs vascularized cardiac allograft survival in a mouse transplant mod...