Dendrimers are hyperbranched macromolecules that can be chemically synthesized to have precise structural characteristics. We used anionic, polyamidoamine, generation 3.5 dendrimers to make novel water-soluble conjugates of D(+)-glucosamine and D(+)-glucosamine 6-sulfate with immuno-modulatory and antiangiogenic properties respectively. Dendrimer glucosamine inhibited Toll-like receptor 4-mediated lipopolysaccharide induced synthesis of pro-inflammatory chemokines (MIP-1 alpha, MIP-1 beta, IL-8) and cytokines (TNF-alpha, IL-1 beta, IL-6) from human dendritic cells and macrophages but allowed upregulation of the costimulatory molecules CD25, CD80, CD83 and CD86. Dendrimer glucosamine 6-sulfate blocked fibroblast growth factor-2 mediated endothelial cell proliferation and neoangiogenesis in human Matrigel and placental angiogenesis assays. When dendrimer glucosamine and dendrimer glucosamine 6-sulfate were used together in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery, they increased the long-term success of the surgery from 30% to 80% (P = 0.029). We conclude that synthetically engineered macromolecules such as the dendrimers described here can be tailored to have defined immuno-modulatory and antiangiogenic properties, and they can be used synergistically to prevent scar tissue formation.
Abstract. We investigate the roles of climate forcings and chaos (unforced variability) in climate change via ensembles of climate simulations in which we add forcings one by one. The experiments suggest that most interannual climate variability in the period 1979-1996 at middle and high latitudes is chaotic. But observed SST anomalies, which themselves are partly forced and partly chaotic, account for much of the climate variability at low latitudes and a small portion of the variability at high latitudes. Both a natural radiative forcing (volcanic aerosols) and an anthropogenic forcing (ozone depletion) leave clear signatures in the simulated climate change that are identified in observations. Pinatubo aerosols warm the stratosphere and cool the surface globally, causing a tendency for regional surface cooling. Ozone depletion cools the lower stratosphere, troposphere and surface, steepening the temperature lapse rate in the troposphere. Solar irradiance effects are small, but our model is inadequate to fully explore this forcing.
Adoptive transfer of Ag-specific T lymphocytes is an attractive form of immunotherapy for cancers. However, acquiring sufficient numbers of host-derived tumor-specific T lymphocytes by selection and expansion is challenging, as these cells may be rare or anergic. Using engineered T cells can overcome this difficulty. Such engineered cells can be generated using a chimeric Ag receptor based on common formats composed from Ag-recognition elements such as αβ-TCR genes with the desired specificity, or Ab variable domain fragments fused with T cell–signaling moieties. Combining these recognition elements are Abs that recognize peptide-MHC. Such TCR-like Abs mimic the fine specificity of TCRs and exhibit both the binding properties and kinetics of high-affinity Abs. In this study, we compared the functional properties of engineered T cells expressing a native low affinity αβ-TCR chains or high affinity TCR-like Ab–based CAR targeting the same specificity. We isolated high-affinity TCR-like Abs recognizing HLA-A2-WT1Db126 complexes and constructed CAR that was transduced into T cells. Comparative analysis revealed major differences in function and specificity of such CAR-T cells or native TCR toward the same antigenic complex. Whereas the native low-affinity αβ-TCR maintained potent cytotoxic activity and specificity, the high-affinity TCR-like Ab CAR exhibited reduced activity and loss of specificity. These results suggest an upper affinity threshold for TCR-based recognition to mediate effective functional outcomes of engineered T cells. The rational design of TCRs and TCR-based constructs may need to be optimized up to a given affinity threshold to achieve optimal T cell function.
We have tested whether affinity-matured TCRs that retain peptide specificity improve the ability of primary human CD8 ؉ T cells to mount antigen-specific responses. We found that TCR affinity correlated with the speed of T-cell responses. High affinity TCR-antigen interactions rapidly initiated T-cell responses, but low affinity TCR/antigen interactions required longer time periods to elicit the same responses. Within the "natural" affinity range, increased TCR-to-antigen affinity correlated with improved ability of T cells to recognize low concentration of antigen. However, affinity-matured TCR with 700-fold enhanced affinity for MHC-toantigen required 100-fold higher antigendensity to initiate T-cell responses than did wild-type TCR. Using modified peptides to reduce the affinity of TCR-toantigen interaction, we demonstrate that affinity-matured TCRs are not defective, being superior to wild-type TCR in recognizing low concentration of modified peptides. These data indicate that enhancing TCR affinity can accelerate the speed of T-cell activation and reduce the ability to recognize low density of MHC-to-peptide antigen. We predict that future studies of the human T-cell repertoire will reveal 2 types of low avidity T cells: fast and slow responders, with high-affinity and low-affinity TCR, respectively. (Blood. 2011;118(2):319-329) IntroductionT cells recognize antigens using the TCR that binds peptides displayed by MHC molecules. Compared with antibodies, the affinity of TCR for MHC-to-peptide is relatively low, with dissociation constants K D ranging from 100-1M. [1][2][3][4] Unlike antibodies, TCRs do not naturally undergo somatic hypermutation to enhance affinity for the TCR-recognized antigen. The reasons for the very limited range of TCR affinities is not fully understood, but might be related to the thymic selection process that eliminates TCRs with high affinity for self MHC-to-peptide while positively selecting low-affinity interactions. 5 In the field of antitumor TCR gene therapy, giving T cells high-affinity TCRs is a major goal for producing T cells capable of attacking tumor cells. 6,7 As most tumor-associated targets are self-antigens that are also expressed in normal tissues, central and peripheral tolerance mechanisms are likely to delete or inactivate T cells expressing high-affinity TCR for these tumor-associated antigens. 8,9 Several strategies have been explored to circumvent tolerance to tumor-associated self-antigens. This includes the use of the natural TCR repertoire of HLA-mismatched donors and HLA-transgenic mice. [10][11][12] In the HLA-mismatched setting the TCR repertoire is not tolerant to peptides presented by non-self HLA molecules, and in the HLA-transgenic setting mice are not tolerant to human proteins and antigens that are not conserved in mice.In vitro affinity maturation provides an additional strategy to select high-affinity TCR. In this setting affinity is not restricted to the physiologic range of naturally selected TCR, but provides an opportunity to enhance TCR affin...
We have previously described the functional activity of a human TCR specific for an HLA-A2-presented peptide derived from the Wilms tumor Ag 1 (WT1). Recent studies showed that the expression and function of human TCR was improved by the introduction of an additional disulfide bond between the α- and β-chains or by the exchange of the human constant region for murine sequences. In this study, we analyzed the functional activity of WT1-TCR variants expressed in Jurkat cells and in primary T cells. The introduction of cysteine residues or murine constant sequences into the WT1-TCR did not result in a global reduction of mispairing with wild-type TCR chains. Instead, the level of mispairing was affected by the variable region sequences of the wild-type TCR chains. The analysis of freshly transduced peripheral blood T cells showed that the transfer of modified TCR constructs generated a higher frequency of Ag-responsive T cells than the transfer of the wild-type TCR. After several rounds of peptide stimulation this difference was no longer observed, as all transduced T cell populations accumulated ∼90% of Ag-responsive T cells. Although the Ag-responsive T cells expressing the modified TCR bound the HLA-A2/WT1 tetramer more efficiently than T cells expressing the wild-type TCR, this did not improve the avidity of transduced T cells nor did it result in a measurable enhancement in IFN-γ production and cytotoxic activity. This indicated that the enhanced tetramer binding of modified WT1-TCR variants was not associated with improved WT1-specific T cell function.
This method of treatment achieves a 54% rate of survival of the hip at forty-five years. Two-thirds of the surviving hips have an excellent prognosis forty to forty-eight years after the index procedure according to the Kellgren and Lawrence score.
The ability to predict times of greater galactic cosmic ray (GCR) fluxes is important for reducing the hazards caused by these particles to satellite communications, aviation, or astronauts. The 11-year solar cycle variation in cosmic rays is highly correlated with the strength of the heliospheric magnetic field. Differences in GCR flux during alternate solar cycles yield a 22-year cycle, known as the Hale Cycle, which is thought to be due to different particle drift patterns when the northern solar pole has predominantly positive (denoted a qA>0 cycle) or negative (qA<0) polarities. This results in the onset of the peak cosmic ray flux at Earth occurring earlier during qA>0 cycles than for qA<0 cycles and hence the peak being more domed for qA>0 and more sharply peaked for qA<0. In this study, we demonstrate that properties of the large-scale heliospheric magnetic field are different during the declining phase of the qA<0 and qA>0 solar cycles, when the difference in GCR flux is most apparent. This suggests that particle drifts may not be the sole mechanism responsible for the Hale Cycle in GCR flux at Earth. However, it is also demonstrated that these polarity-dependent heliospheric differences are evident during the space-age but much less clear in earlier data: using geomagnetic reconstructions, it is shown that for the period of 1905 -1965, alternate polarities do not give as significant a difference during the declining phase of the solar cycle. Thus we suggest that the 22-year cycle in cosmic ray flux is at least partly the result of direct modulation by the heliospheric magnetic field and that this effect may be primarily limited to the grand solar maximum of the space-age.
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