We here report the molecular cloning of a novel family of killer-cell lectin-like (KLR) receptors in the rat and the mouse, termed KLRI. In both species, there are two members, KLRI1 and KLRI2. While the extracellular lectin-like domains of KLRI1 and KLRI2 are similar [74% (rat) and 83% (mouse) amino acid identity], they differ intracellularly. KLRI1 has two immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic domain, suggesting an inhibitory function. KLRI2 has no ITIM, but a positively charged lysine residue in the transmembrane region, suggesting association with activating adapter molecules. Klri1 and Klri2 are localized within the natural killer (NK) cell gene complex on rat chromosome 4 and mouse chromosome 6. By RT-PCR and Northern blot analysis KLRI1 and KLRI2 were selectively expressed by NK cells in both rat and mouse. Epitope-tagged expression constructs of rat KLRI1 and rat KLRI2 induced surface expression of a nondisulphide-linked protein of M(r) 36,000/39,000 and M(r) 34,000, respectively.

Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.

Blockade of antigen nonspecific costimulatory signals is a promising approach for the treatment of autoimmune diseases including systemic lupus erythematosus (SLE). CTLA4Ig, an antagonist of the CD28/B7 costimulatory interaction, effectively prevents SLE onset in several murine models and, when used in combination with cyclophosphamide, can induce remission of active SLE nephritis. In this review we describe the known mechanisms of action of CTLA4Ig both in normal immunity and in autoimmune disease models and address issues about its activity that still need to be resolved. We discuss the preclinical use of CTLA4Ig in murine SLE models and the rationale for a clinical trial in SLE patients.

Clinical trials show that hormone therapy (HT) is an effective treatment for vasomotor symptoms and vaginal dryness. HT improves other symptoms including sleep and quality of life in women who have menopause symptoms. In the Women's Health Initiative controlled clinical trials, both estrogen therapy (ET) and estrogen plus progestin therapy (EPT) reduced fracture risk, neither reduced the risk of heart disease, and both increased the risk of stroke, deep vein thrombosis, and dementia. EPT, but not ET, increased breast cancer risk and reduced colon cancer risk. Differences between EPT and ET may reflect chance, baseline differences between the EPT and ET cohorts, or a progestin effect. Studies of younger women and lower HT doses with intermediate endpoints are beginning.

We here report the cDNA sequences of 11 new rat Ly49 genes with full and three with incomplete open reading frames. Although obtained from different inbred rat strains, these as well as six previously published cDNA represent non-allelic genes matching different loci in the Brown Norway (BN) rat genome, which is predicted to contain 34 Ly49 loci distributed over the distal part of the NK cell gene complex. Some of the cloned genes appear to be mutated to non-function in the BN genome, which harbors additional genes with full open reading frames, suggesting at least 26 non-allelic functional Ly49 genes in the rat. Of the encoded receptors, 13 are predicted to be inhibitory, eight to be activating, whereas five may be both ('bifunctional'). Phylogenetic analysis bears evidence of a highly dynamic genetic region, in which only the most distally localized Ly49 gene has a clear-cut mouse ortholog. In phylograms, the majority of the genes cluster into three subgroups with the genes mapping together, defining three chromosomal regions that seem to have undergone recent expansions. When comparing the lectin-like domains, the receptors form smaller subgroups, most containing at least one inhibitory and one activating or 'bifunctional' receptor, where close sequence similarities suggest recent homogenization events.