The Role of the Fc Region in CD70-specific Antibody Effects on Cardiac Transplant Survival

Background: The role of the CD70-specific antibody and the mechanisms by which it extends transplant survival are not known. Methods: Fully major histocompatibility complex-mismatched heterotopic heart transplantation (BALB/c to C57BL/6) was performed. Treated mice received intraperitoneal injections of wild-type (WT) CD70-specific antibody (FR70) or IgG1 or IgG2a chimeric antibodies on days 0, 2, 4, and 6 posttransplantation. Results: WT FR70 antibody significantly extended heart transplant survival to 19 days compared with untreated mice (median survival time [MST]=10 days). Graft survival using the nondepleting IgG1 antibody was significantly shorter (MST=14 days), whereas the survival using depleting IgG2a antibody (MST=18) was similar to that using WT FR70. The FR70 and IgG2a antibodies demonstrated a greater efficiency of fixing mouse complement over the IgG1 variant in vitro. CD4 and CD8 T-cell graft infiltration was reduced with treatment; however, this was most pronounced with WT FR70 and IgG2a antibody therapy compared with the IgG1 chimeric variant. Circulating donor-specific IgG alloantibodies were initially reduced with WT FR70 treatment (day 8 posttransplantation) but increased at days 15 and 20 posttransplantation to the level detected in untreated controls. Conclusion: We conclude that WT (FR70) and the IgG2a depleting variant of CD70-specific antibody reduce graft infiltrating CD4 and CD8 T cells, transiently reduce serum alloantibody levels, and extend graft survival. In contrast, the nondepleting IgG1 variant of this antibody showed lower efficacy. These data suggest that a depleting mechanism of action and not merely costimulation blockade plays a substantial role in the therapeutic effects of CD70-specific antibody

Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice

Destruction of pancreatic islets in type 1 diabetes is caused by infiltrating, primed and activated T cells. In a clinical setting this autoimmune process is already in an advanced stage before intervention therapy can be administered. Therefore, an effective intervention needs to reduce islet inflammation and preserve any remaining islet function. In this study we have investigated the role of targeting activated T cells in reversing autoimmune diabetes. A combination therapy consisting of CD25-, CD70- and CD8-specific monoclonal antibodies was administered to non-obese diabetic (NOD) mice with either new-onset diabetes or with advanced diabetes. In NOD mice with new-onset diabetes antibody combination treatment reversed hyperglycaemia and achieved long-term protection from diabetes (blood glucose 50% of mice. In contrast, in the control, untreated group blood glucose levels continued to increase and none of the mice were protected from diabetes (P < 0·0001). Starting therapy early when hyperglycaemia was relatively mild proved critical, as the mice with advanced diabetes showed less efficient control of blood glucose and shorter life span. Histological analysis (insulitis score) showed islet preservation and reduced immune infiltration in all treated groups, compared to their controls. In conclusion, antibody combination therapy that targets CD25, CD70 and CD8 results in decreased islet infiltration and improved blood glucose levels in NOD mice with established diabetes

Acoustic observations of zooplankton in lakes using a Doppler current profiler

In this paper we test the usefulness of acoustic backscatter measurements from a 614 kHz Acoustic Doppler Current Profiler (ADCP) for the qualitative and quantitative characterisation of zooplankton distributions in lakes. ADCP-based backscatter estimates were compared with frequent net hauls obtained during a calibration experiment in which the acoustic backscatter was strongly dominated by vertical migrating Chaoborus flavicans larvae.2. The correlation between backscatter estimates and the C. flavicans concentration was very good. Vertical swimming speed of larvae, measured directly by the ADCP, was up to a maximum of 5 mm s−1 and agreed very well with the observed vertical movement of the backscatter contour lines. Although the strong backscatter from C. flavicans overwhelmed the signal from the remaining zooplankton, a good correlation between backscatter strength and the total remaining zooplankton concentration, dominated by Cyclops spp., was found for the depth and time intervals where no C. flavicans were present.3. In addition to the calibration experiment, longer-term ADCP measurements from different lakes revealed a strong temporal correlation between the onset of the up- and downward migration of zooplankton and the local sunset and sunrise.4. We conclude that ADCPs can be used to monitor plankton distributions both temporally and spatially. It also seems possible to estimate plankton densities after appropriate calibration

Upper Bounds on the Computational Power of an Optical Model of Computation

We present upper bounds on the computational power of an optical model of computation called the C2-CSM

The complexity of problems on implicitly represented inputs

Abstract. Highly regular data can be represented succinctly by various kinds of implicit data structures. Many problems in P are known to be hard if their input is given as circuit or Ordered Binary Decision Diagram (OBDD). Nevertheless, in practical areas like CAD and Model Checking, symbolic algorithms using functional operations on OBDD-represented data are well-established. Their theoretical analysis has mostly been restricted to the number of functional operations yet. We show that Pcomplete problems have no symbolic algorithms using a polylogarithmic number of functional operations, unless P=NC. Moreover, we complement PSPACE-hardness results for problems on OBDD-represented inputs by fixed-parameter intractability results, where the OBDD width serves as the fixed parameter.