Although immunosuppressive therapy minimizes the risk of graft failure due to acute rejection, transplant-associated arteriosclerosis of the coronary arteries remains a significant obstacle to the long-term survival of heart transplant recipients. The participation of specific inflammatory cell types in the genesis of this lesion was examined in a mouse model in which carotid arteries were transplanted across multiple histocompatibility barriers into seven mutant strains with immunologic defects. An acquired immune response-with the participation of CD4+ (helper) T Transplant-associated arteriosclerosis is the major cause of cardiac allograft failure and consequent mortality after the first postoperative year (1), and it appears to be a significant problem in the long-term survival of kidney transplants (2). In contrast with common arteriosclerosis, the lesion associated with transplant arteriosclerosis involves the artery in a concentric rather than eccentric fashion and often extends beyond the epicardial coronary arteries to the secondary and tertiary intramyocardial branches (3). Lipid accumulation is less common in the early development of the transplant-associated lesion (4), and the tempo of the disease is faster (2). Inflammatory cells infiltrate the blood vessels of the transplanted organ (5) and produce cytokines, growth factors, and chemotactic agents (6)(7)(8)
Recent gene targeting studies indicate that the plasminogen system is implicated in cell migration and matrix degradation during arterial neointima formation and atherosclerotic aneurysm formation. This study examined whether plasmin proteolysis is involved in accelerated posttransplant arteriosclerosis (graft arterial disease). Donor carotid arteries from wild-type B10.A2R mice were transplanted into either plasminogen wild-type (Plg ϩ / ϩ ) or homozygous plasminogen-deficient (Plg Ϫ / Ϫ ) recipient mice with a genetic background of 75% C57BL/6 and 25% 129. Within 15 d after allograft transplantation, leukocytes and macrophages infiltrated the graft intima in Plg ϩ / ϩ and Plg Ϫ / Ϫ recipient mice to a similar extent. In Plg ϩ / ϩ recipients, the elastic laminae in the transplant media exhibited breaks through which macrophages infiltrated before smooth muscle cell proliferation, whereas in Plg Ϫ / Ϫ recipients, macrophages failed to infiltrate the transplant media which remained structurally more intact.
To define the role of specific gene deletions and mutations in the development of transplant arteriosclerosis, we generated an accelerated model of the disease in mice. Carotid arteries were transplanted between B.10A(2R) (H-2h2) donor mice and C57BL/6J (H-2b) recipients and compared with arteries isografted between H-2b mice. Immunosuppressive drugs were not used. Within 7 days, the allografted carotid artery formed a neointima composed of mononuclear leukocytes (CD45+) that were predominantly monocytes or macrophages (ie, CD11b+ cells with single-lobed nuclei). CD4+ and CD8+ cells were present as well. By 30 days, the neointima became exuberant, and mononuclear leukocytes were largely replaced by smooth muscle cells. Cells staining for proliferating-cell nuclear antigen were abundantly present in the intima at both early and late time points, indicating the proliferation of mononuclear leukocytes and smooth muscle cells. The area of the intima increased from day 7 to day 30 (P < .0005), as did the number of nuclei (P = .0005), but the density of the nuclei decreased (P = .02), suggesting the formation of extracellular matrix. Six of the eight isografts formed no neointima, and in samples from the remaining two, a single layer of smooth muscle neointimal cells covered just a portion of the vessel circumference. This model, which reproduces many of the features of human transplant arteriosclerosis but at an accelerated pace, should prove useful for determining the roles in transplant arteriosclerosis of genes that code for components of immunologic and inflammatory responses.
Vascular smooth muscle and the associated connective tissue matrix are central to blood vessel integrity and function, and activation of vascular smooth muscle cells is characteristic of arteriosclerosis and hypertension. After vessel wall injury, smooth muscle cells are transformed from a contractile, quiescent phenotype to a proliferative, migratory phenotype that secretes abundant extracellular matrix (1). Vascular smooth muscle cells are subject to complex regulation by soluble extracellular signals provided by growth factors, cytokines, and vasoactive agents as well as cell-cell and cell-matrix interactions (1). Therefore, factors controlling smooth muscle cell behavior, including migration, proliferation, and lipid metabolism, are critical to the pathogenesis of cardiovascular disease. Cell surface signal transduction and adhesion molecules such as vascular cell adhesion molecule-1 (2) and the 1 and 3 integrins (3, 4) have been implicated in the modulation of smooth muscle cell function. Previous studies from our laboratory indicate that the proteoglycan CD44 may also mediate vascular smooth muscle cell activation during vascular remodeling (5).The CD44 transmembrane glycoprotein exists in a variety of isoforms generated by alternative splicing of one (or more) of 10 variable exons in the extracellular domain (6, 7). CD44 is the principal cell receptor for hyaluronic acid (8) and interacts with other extracellular matrix molecules including osteopontin, collagen, and fibronectin (9, 10). Present on many cell types, CD44 has been correlated with cell proliferation (11, 12) and oncogenic transformation (13). Ligation of CD44 stimulates cytokine release by monocytes/macrophages (14, 15), and it may modulate T lymphocyte activation signals (16,17). In a variety of cell systems CD44 imparts a novel cellular adhesive and/or migratory phenotype to transfected cells (9,18,19), and an isoform containing the sixth variable exon (v6) confers metastatic potential to rat pancreatic carcinoma cells (20). The importance of CD44 in vivo has also been demonstrated in a mouse model in which an antisense CD44 transgene is expressed selectively under the control of a keratinocyte-specific promoter (21). Suppression of CD44 expression inhibits keratinocyte proliferation and results in abnormal hyaluronate metabolism in the skin. Moreover, CD44 is induced on smooth muscle cells after vascular injury, and it may mediate the proliferative effects of hyaluronate (5).Our laboratory has developed a mouse model of transplantassociated arteriosclerosis in which a carotid artery loop is transplanted between inbred strains in syngeneic and allogeneic combinations (22). Lesion development depends on an acquired immune response and begins with infiltration of inflammatory cells, after which follows accumulation of smooth muscle cells in the neointima (23). In the present study we evaluated CD44 cell surface protein expression in vivo during the pathogenesis of transplant arteriosclerosis in order to understand the role of CD44 in modula...
The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.
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