Context Severe acute respiratory syndrome (SARS) is a new clinical entity for which no effective therapeutic strategy has been developed.Objective To provide preliminary results on the potential therapeutic benefit and tolerability of interferon alfacon-1 plus corticosteroids for SARS. Design, Setting, and PatientsOpen-label study of 22 patients diagnosed as having probable SARS at North York General Hospital, Toronto, Ontario, between April 11 and May 30, 2003.Interventions Thirteen patients were treated with corticosteroids alone and 9 patients were treated with corticosteroids plus subcutaneous interferon alfacon-1. Main Outcome MeasuresClinical parameters, including oxygen saturation and requirement, laboratory measures, and serial chest radiography results. ResultsResolution of fever and lymphopenia were similar between the 2 treatment groups. Of the 13 patients treated with corticosteroids alone, 5 (38.5%) were transferred to the intensive care unit, 3 (23.1%) required intubation and mechanical ventilation, and 1 (7.7%) died. Of the 9 patients in the interferon alfacon-1 treatment group, 3 (33.3%) were transferred to the intensive care unit, 1 (11.1%) required intubation and mechanical ventilation, and none died. The interferon alfacon-1 treatment group had a shorter time to 50% resolution of lung radiographic abnormalities (median time, 4 days vs 9 days; P=.001), had better oxygen saturation (P=.02), resolved their need for supplemental oxygen more rapidly (median, 10 days vs 16 days; P=.02), had less of an increase in creatine kinase levels (P=.03), and showed a trend toward more rapid resolution of lactate dehydrogenase levels compared with the group receiving corticosteroids alone. ConclusionsIn this preliminary, uncontrolled study of patients with SARS, use of interferon alfacon-1 plus corticosteroids was associated with reduced diseaseassociated impaired oxygen saturation, more rapid resolution of radiographic lung abnormalities, and lower levels of creatine kinase. These findings suggest that further investigation may be warranted to determine the role of interferon alfacon-1 as a therapeutic agent for the treatment of SARS.

Most tissues of the body harbor resident macrophages. Yet, macrophages are phenotypically and functionally heterogeneous, a reflection of the diversity of tissue environments in which they reside. In addition to maintaining tissue homeostasis and responding to invading pathogens, macrophages contribute to numerous pathological processes, making them an attractive potential target for therapeutic intervention. To do so, however, will require a detailed understanding of macrophage origins, the mechanisms that maintain them, and their functional attributes in different tissues and disease contexts.Macrophage ontology has long engendered controversy 1,2 . Nevertheless, the concept that tissue macrophages develop exclusively from circulating bone marrow-derived monocytes has prevailed for nearly a half century 3 . Accumulated evidence, however, including recent studies using sophisticated fate-mapping approaches, have determined that some tissue macrophages and their precursors are established embryonically in the yolk sac (YS) and fetal liver before the onset of definitive hematopoiesis [4][5][6][7][8][9][10][11] . Regardless of their origin, tissue macrophages can maintain themselves in adulthood by self-renewal independent of blood monocytes 12,13 .Gene-expression profiling of macrophage populations from several tissues has established that only a small number of transcripts are expressed by all macrophages 14 , indicating the importance of the context provided by the tissue when studying macrophage function in homeostasis and disease. The normal arterial wall contains many tissue resident macrophages that contribute crucially to immunity, tissue homeostasis and wound healing following injury 15. However, the regulatory networks, ancestry and mechanisms that maintain arterial macrophages remain unknown.Using gene expression analysis, we show that arterial macrophages constitute a distinct population among tissue macrophages. Multiple fate mapping approaches demonstrated that arterial macrophages arise embryonically from CX 3 CR1 + precursors and postnatally from bone marrow-derived monocytes that colonize the tissue during a brief period immediately after birth.In adulthood, arterial macrophages were maintained by CX 3 CR1-CX 3 CL1 interactions and local proliferation without significant further contribution from blood monocytes. Self-renewal also sustained arterial macrophages after severe depletion during polymicrobial sepsis, rapidly restoring them to functional homeostasis. ResultsPhenotype and gene expression profiling of arterial macrophages. (Fig. 1a).Principal component analysis revealed a distinct transcriptome in arterial macrophages, which clustered near other macrophage populations including microglia, alveolar macrophages, and splenic red pulp macrophages, as characterized by the Immunological Genome Consortium (Fig. 1b, Supplementary Fig. 1a) 14. Stringent comparison of gene-expression profiles among arterial, brain, alveolar and splenic red pulp macrophages revealed 212 transcripts that were at ...

Severe acute respiratory syndrome (SARS) is a life-threatening infectious disease which has been difficult to study and treat because of the lack of a readily available animal model. Intranasal infection of A/J mice with the coronavirus murine hepatitis virus strain 1 (MHV-1) produced pulmonary pathological features of SARS. All MHV-1-infected A/J mice developed progressive interstitial pneumonitis, including dense macrophage infiltrates, giant cells, and hyaline membranes, resulting in death of all animals. In contrast, other mouse strains developed only mild transitory disease. Infected A/J mice had significantly higher cytokine levels, particularly macrophage chemoattractant protein 1 (MCP-1/CCL-2), gamma interferon, and tumor necrosis factor alpha. Furthermore, FGL2/fibroleukin mRNA transcripts and protein and fibrin deposits were markedly increased in the lungs of infected A/J mice. These animals developed a less robust type I interferon response to MHV-1 infection than resistant C57BL/6J mice, and treatment with recombinant beta interferon improved survival. This study describes a potentially useful small animal model of human SARS, defines its pathogenesis, and suggests treatment strategies.

Hepatitis B after liver transplantation is often fatal, and no proven medical therapy exists for this condition. We chose to study the potential efficacy of lamivudine therapy for patients with chronic hepatitis B after liver transplantation. Fifty-two patients with chronic hepatitis B after liver transplantation were treated in an open label, multicenter study. Each had detectable hepatitis B virus (HBV) DNA in serum and 45 (87%) had detectable serum hepatitis B e antigen before treatment. Patients were treated for 52 weeks with lamivudine (100 mg daily). The primary endpoint was undetectability of HBV DNA; secondary endpoints included normalization of serum alanine transaminase (ALT) levels, disappearance of hepatitis B e antigen, and improvement in liver histology. After treatment, 60% of patients had undetectable HBV DNA by solution hybridization assay, 14 (31%) of the initially positive patients lost hepatitis B e antigen; hepatitis B surface antigen was undetectable in 3 (6%); and serum ALT levels normalized in 71%. Blinded histological assessments showed improvement in the histological activity index (P ‫؍‬ .007 for periportal necrosis, .001 for lobular necrosis, and .013 for portal inflammation). YMDD variants of HBV, potentially associated with drug resistance, were detected in 14 (27%) of the patients. Repeat liver biopsies in 7 patients with the mutated virus were unchanged in 2, improved in 2, and worse in 3. We conclude that lamivudine is a potentially effective therapy for hepatitis B after liver transplantation. (HEPATOLOGY 1999;29:1581-1586.)

ObjectiveThis study defined negative outcomes of solid organ transplantation, proposed a new classification of complications by severity, and applied the classification to evaluate the results of orthotopic liver transplantation (OLT). Summary and Background DataThe lack of uniform reporting of negative outcomes has made reports of transplantation procedures difficult to interpret and compare. In fact, only mortality is well reported; morbidity rates and severity of complications have been poorly described. MethodsBased on previous definition and classification of complications for general surgery, a new classification for transplantation in four grades is proposed. Results including risk factors of the first 215 OLTs performed at the University of Toronto have been evaluated using the classification. ResultsAll but two patients (99%) had at least one complication of any kind, 92% of patients surviving more than 3 months had grade 1 (minor) complications, 74% had grade 2 (life-threatening) complications, and 30% had grade 3 (residual disability or cancer) complications. Twenty-nine per cent of patients had grade 4 complications (retransplantation or death). The most common grade 1 complications were steroid responsive rejection (69% of patients) and infection that did not require antibiotics or invasive procedures (23%). Grade 2 complications primarily were infection requiring antibiotics or invasive procedures (64%), postoperative bleeding requiring >3 units of packed red cells (35%), primary dysfunction (26%), and biliary disease treated with antibiotics or requiring invasive procedures (18%). The most frequent grade 3 complication was renal failure, which is defined as a permanent rise in serum creatinine levels 2 twice the pretransplantation values (1 1%). Grade 4 complications (retransplantation or death) mainly were infection (14%) and primary dysfunction (11%). Comparison between the first and last 50 OLTs of the series indicates a significant decrease in the mean number of grade 1 and 2 complications. This was partially a result of better medical status of patients at the time of transplantation. Using univariate and multivariate analyses of risk factors, the best predictor of grade 1 complications was donor 109

Mice with targeted deletion of fibrinogen‐like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild‐type recipients reconstituted with fgl2−/− bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, T helper 1 (Th1) polarization, and increased numbers of antibody‐producing B cells following immunization with T‐independent antigens. Dendritic cells (DC) were more abundant in fgl2−/− mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2−/− mice, but their suppressive activity was significantly impaired. Antibody to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited DC maturation and induced apoptosis of B cells through binding to the low affinity FcγRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease. This work was supported in part by grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research.

No abstract

Fibrinogen-like protein 2 (fgl2)/fibroleukin is a member of the fibrinogen-related protein superfamily. In addition to its established role in triggering thrombosis, it is known to be secreted by T cells. The soluble fgl2 (sfgl2) protein generated in a baculovirus expression system bound to both T cells and bone marrow-derived dendritic cells (DC) in a specific manner. sfgl2 exhibited immunomodulatory properties capable of inhibiting T cell proliferation stimulated by alloantigens, anti-CD3/anti-CD28 mAbs, and Con A in a dose-dependent manner; however, it had no inhibitory effects on CTL activity. The time- and dose-dependent inhibitory effect of sfgl2 on alloreactive T cell proliferation could be neutralized by a mAb against mouse fgl2. Polarization toward a Th2 cytokine profile with decreased production of IL-2 and IFN-γ and increased production of IL-4 and IL-10 was observed in sfgl2-treated allogeneic cultures. Exposure of immature DC to sfgl2 abrogated the expression of CD80high and MHC class IIhigh molecules and markedly inhibited NF-κB nuclear translocation, thus inhibiting their maturation. sFgl2-treated DC had an impaired ability to stimulate allogeneic T cell proliferation. Maximal inhibition of proliferation was observed when allogeneic T cells were cultured with sfgl2-treated DC and sfgl2 protein was added in the culture. These data provide the first evidence to demonstrate that sfgl2 exerts immunosuppressive effects on T cell proliferation and DC maturation.