The United States and Canadian Academy of Pathology Lippincott Williams and Wilkins publishes Laboratory Investigation

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		ANTIGEN PRESENTATION IN THE CNS: The brain is commonly considered a site of immune privilege, possibly caused by high levels of inhibitory cytokines (eg, TGF-b3). The brain also has a paucity of antigen presenting cells (APC) ie, cells capable of expressing high levels of class I and class II MHC molecules and using these molecules to display antigenic peptides to T lymphocytes. Recognition of peptide-MHC complexes on the surface of an APC is required to initiate cell-mediated immune responses. Although MHC molecule expression is not sufficient for a cell to serve as an APC, it is a necessary component, and only cell types that display high levels are capable of being APC. Despite the absence of constitutive MHC molecule expression, numerous cells within the inflamed CNS, in which the MHC-inducing cytokine IFN-g will be produced, do appear to have the requisite levels of expression of MHC molecules. Some of these cells are infiltrating leukocytes, but some are indigenous to the brain, including microglia (a bone marrow derived cell of the mononuclear-phagocyte lineage), microvascular endothelial cells, and, it has commonly been thought, astrocytes. Many cell types respond to IFN-g in vitro to express MHC molecules but fewer respond in situ. The experimental system used to suggest that astrocytes do express MHC molecules in situ has been rodent models of brain inflammation (eg, experimental autoimmune encephalomyelitis) and immunohistochemical analysis. Both components of this experiment are potentially problematic because inflammation can distort normal cell and tissue architecture and, unless extended to the electron microscope level, immunohistochemistry is of limited resolution. These two factors may lead to an incorrect assignment of positive staining being made. In this issue, Horwitz and colleagues (Lab Invest 1999;79:235-242) have re-examined this question using better tools. Rather than induce inflammation, high intracranial levels of IFN-g were achieved through expression of a CNS-specific promoter-driven IFN-g transgene.This lead to upregulation of MHC molecule expression without the confounding variable of inflammation. Second, the investigators have improved resolution of detection by using confocal two color immunofluorescence microscopy instead of conventional immunohistochemistry. The surprising answer is clear cut: microglia and microvascular endothelial cells do express MHC molecules but astrocytes do not. Astrocyte processes only appear positive where they abut upon positive endothelial cells, ie, where endothelial staining can be mistaken for astrocytic staining. What does this say about the initiation of autoimmune CNS diseases like EAE or multiple sclerosis? It would now seem less likely that T cells recognize their cognate antigens on astrocytes. It still remains possible that astrocytes respond to signals other than IFN-g, but this seems unlikely. The best current model is that antigens expressed on endothelial cells are recognized by circulating T cells, perhaps recruiting specific T cells into the CNS where the T cells can be further activated and expanded by antigen recognition on resident microglia or on newly recruited APC such as blood monocytes or dendritic cells. Additional experiments are needed to test these ideas. Detailed in Vivo Analysis of Interferon-(gamma) Induced Major Histocompatibility Complex Expression in the Central Nervous System: Astrocytes Fail to Express Major Histocompatibility Complex Class I and II Molecules Marc S. Horwitz, Claire F. Evans, F. George Klier, and Michael B.A. Oldstone MONOCYTES AND REPERFUSION INJURY: Ischemia caused by vascular thrombosis (or experimental ligation) is a well recognized cause of hypoxic tissue injury. More than 30% of all deaths in the United States are caused by ischemic injury of the myocardium. With the advent of thrombolytic therapy to treat acute myocardial ischemia, it has become widely appreciated that reperfusion of hypoxic tissue can cause additional injury primarily due, paradoxically, to oxygen. In rodents, an important component of oxidative injury upon reperfusion may be mediated by reactive oxygen intermediates (ROI) generated within the hypoxic tissue itself due to the ischemia-mediated proteolytic conversion of xanthine dehydrogenase to xanthine oxidase. In humans, this does not happen, and the major source of ROI is infiltrating neutrophils. Neutrophils generate ROI via the NADPH oxidase system as part of their |P`respiratory burst.|P' This has led to the notion that the extent of reperfusion injury could be limited if one prevented neutrophil recruitment. In this month\'s issue, Ono and colleagues (Lab Invest 1999;79:195-204) have identified a new player in reperfusion injury, the blood monocyte. Specifically, these workers have shown that, in a rat model, myocardium subjected to ischemia and reperfusion produced the monocyte recruiting chemokine, monocyte chemoattractant protein-1 (MCP-1), and that monocytes constituted part of the developing inflammatory infiltrate. Neutralizing antibody to MCP-1 not only reduces monocyte recruitment but also reduces the amount of myocardium that is damaged after 24 hours of reperfusion. These data suggest that blockade of monocyte recruitment may be as important as blockade of neutrophil recruitment for reducing the extent of reperfusion injury after thrombolysis. In general, neutrophils and monocytes use the same adhesion molecules but respond differentially to various chemokines generated at sites of inflammation. Thus the choice of molecular target selected by the authors for their study, MCP-1, is a logical way to separate the recruiment of neutrophils from that of monocytes. However, if leukocyte blockade is eventually translated into therapy, it may be preferable at that stage to select a common target, eg, E selectin or intercilial adhesion molecule-1 (ICAM-1), to maximally protect tissues from reperfusion injury. Prevention of Myocardial Reperfusion Injury in Rats by an Antibody against Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 Koh Ono, Akira Matsumori, Yutaka Furukawa, Hideki Igata, Tetsuo Shioi, Kouji Matsushima, and Shigetake Sasayama A LYMPHATIC ENDOTHELIAL ORIGIN OF KAPOSI'S SARCOMA: Kaposi's sarcoma (KS), previously noted to be a tumor of low occurrence, is currently the most common neoplasm in patients suffering with AIDS. KS lesions are comprised of irregular vascular spaces in early stages and by spindle cells in latter stages of the disease. The origin of KS tumor cells has been a matter of controversy and debate over the past several years and many mesenchymal cell types have been proposed. The recent findings of several endothelial markers (including CD31, CD34, CD36, and KDR) on KS tumor cells has strengthened the notion that the endothelial cell is the cell of origin of KS. However, the lack of Pal-E and eNOS expression has brought into question the endothelial origin of this tumor. Recently, several new endothelial markers have been identified and characterized. The expressions of two such proteins, VEGFR3 (VEGF-C receptor, flt-4) and podoplanin (a membrane glycoprotein), have been found to be restricted to lymphatic endothelium. In this issue, Weninger et al (Lab Invest 1999;79:243-251) demonstrate that KS tumor cells in tissue samples of KS lesions express these two markers of lymphatic endothelium as well as the general endothelial marker, CD31, strongly suggesting that KS is derived from lymphatic endothelium. Four KS-derived cell cultures tested were found not to express these two markers or CD31 and CD34, suggesting that the cultured cells either are not related to the tumor cells in KS, or that they have lost these markers in vitro. In the latter case, the loss of expression of these markers may be indicative of a more generalized change of cellular phenotype in vitro, which could lead to erroneous conclusions regarding KS cell biology including growth factor and cytokine responsiveness and viral susceptibility. The findings of this study will be beneficial in characterizing cultured cells derived from KS lesions and directing and interpreting future investigations of growth factor expression in KS lesions (such as expression of VEGF-C and VEGF-D, ligands for VEGFR3)and viral susceptibility. Expression of Vascular Endothelial Growth Factor Receptor-3 and Podoplanin Suggests a Lymphatic Endothelial Cell Origin of Kaposi\'s Sarcoma Tumor Cells Wolfgang Weninger, Taina A. Partanen, Silvana Breiteneder-Geleff, Christoph Mayer, Heinrich Kowalski, Michael Mildner, Johannes Pammer, Michael Stürzl, Dontscho Kerjaschki, Kari Alitalo, and Erwin Tschachler INHIBITING PRIMARY GROWTH OF CANCER? Matrix metalloproteinases (MMP) are endopeptidases that play a key role in the invasion, metastasis, and metastatic growth of malignant tumors. Extracellular matrix remodeling by MMP activity is thought to be necessary for neovascularization (angiogenesis) of primary and metastatic tumor foci. Tissue inhibitors of metalloproteinases (TIMP) inhibit the proteolytic activity of MMP, and can thereby inhibit tumor invasion and metastasis. Host overexpression of TIMP can inhibit tumor growth, invasion, and metastases, as demonstrated in transgenic mice overexpressing TIMP-1. However, TIMP expression can stimulate mitogenesis in some tumor cell lines, raising the possibility that there are important intracellular effects of TIMP within malignant cells. In the current issue, Martin et al (Lab Invest 1999;79:225-234) investigated the effects of TIMP-1 on murine hepatocarcinogenesis. Transgenic mice, over- or underexpressing TIMP-1, were cross-bred with SV40 T antigen-expressing mice that exhibit a propensity for developing hepatocellular carcinomas. Liver tissues were examined for TIMP-1 mRNA expression and MMP enzyme activity, extracellular matrix status, and hepatocyte proliferation. TIMP-1 overexpression inhibited hepatocyte proliferation in SV40 T antigen-positive mice but did not alter apoptotic indices or extracellular matrix composition. Primary tumor angiogenesis in the developing hepatocellular carcinomas was decreased in TIMP-1 overexpressing mice, whereas it was increased when TIMP-1 levels were reduced. The authors concluded that MMP inhibitors play a key role in primary tumor growth and angiogenesis, and that pharmaceutical use of MMP inhibitors at early stages of cancer may be warranted. This study did not reveal how cellular proliferation within malignant liver foci was affected, nor did it determine how angiogenesis was so greatly affected without alterations in extracellular matrix composition or structure. However, these in vivo studies provide provocative evidence that enhancing local TIMP level may inhibit primary growth of cancer at a stage earlier than invasion and metastasis. Transgenic TIMP-1 Inhibits Simian Virus 40 T Antigen\NInduced Hepatocarcinogenesis by Impairment of Hepatocellular Proliferation and Tumor Angiogenesis David Charles Martin, Otto Hernando Sanchez-Sweatman, Andrew Tri-Van Ho, Danwanti Sharmela Inderdeo, Ming-Sound Tsao, Rama Khokha