Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-γ) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63129/1/15258160050079407.pd

Supersymmetric Sum Rules for Electromagnetic Multipoles

We derive model independent, non-perturbative supersymmetric sum rules for the magnetic and electric multipole moments of any theory with N=1 supersymmetry. We find that in any irreducible N=1 supermultiplet the diagonal matrix elements of the l-multipole moments are completely fixed in terms of their off-diagonal matrix elements and the diagonal (l-1)-multipole moments.Comment: 10 pages, plain Te

Running Gauge Couplings and Thresholds in the Type II Superstring

A distinctive feature of string unification is the possibility of unification by a non-simply-laced group. This occurs most naturally in four dimensional type~II string models where the gauge symmetry is realized by Kac-Moody algebras at different levels. We investigate the running coupling constants and the one-loop thresholds for such general models. As a specific case, we examine a $\rm SU(3)\times U(1)\times U(1)$ model and find that the threshold corrections lead to a small $6\%$ increase in the unification scale.Comment: 12 pages, IFP-432-UN

What is the effect of a decision aid in potentially vulnerable parents? Insights from the head CT choice randomized trial.

ObjectiveTo test the hypotheses that use of the Head CT Choice decision aid would be similarly effective in all parent/patient dyads but parents with high (vs low) numeracy experience a greater increase in knowledge while those with low (vs high) health literacy experience a greater increase in trust.MethodsThis was a secondary analysis of a cluster randomized trial conducted at seven sites. One hundred seventy-two clinicians caring for 971 children at intermediate risk for clinically important traumatic brain injuries were randomized to shared decision making facilitated by the DA (n = 493) or to usual care (n = 478). We assessed for subgroup effects based on patient and parent characteristics, including socioeconomic status (health literacy, numeracy and income). We tested for interactions using regression models with indicators for arm assignment and study site.ResultsThe decision aid did not increase knowledge more in parents with high numeracy (P for interaction [Pint ] = 0.14) or physician trust more in parents with low health literacy (Pint  = 0.34). The decision aid decreased decisional conflict more in non-white parents (decisional conflict scale, -8.14, 95% CI: -12.33 to -3.95; Pint  = 0.05) and increased physician trust more in socioeconomically disadvantaged parents (trust in physician scale, OR: 8.59, 95% CI: 2.35-14.83; Pint  = 0.04).ConclusionsUse of the Head CT Choice decision aid resulted in less decisional conflict in non-white parents and greater physician trust in socioeconomically disadvantaged parents. Decision aids may be particularly effective in potentially vulnerable parents

t cell mediated rejection of human cd34 cells is prevented by costimulatory blockade in a xenograft model

Abstract A xenograft model of stem cell rejection was developed by co-transplantating human CD34 + and allogeneic CD3 + T cells into NOD-scid ɣ-chain null mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34 + cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34 + cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day –1 to +27 (group A), from day –1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls ( P  = .03). Retransplantation of group A mice with same CD34 + cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34 + cells may be facilitated by treatment with abatacept and late stem cell boost

Vacua of M-theory and string theory

We argue that supersymmetric higher-dimension operators in the effective actions of M-theory and IIB string theory do not affect the maximally supersymmetric vacua: $adS_4\times S^7$ and $adS_7\times S^4$ in M-theory and $adS_5\times S^5$ in IIB string theory. All these vacua are described in superspace by a fixed point with all components of supertorsion and supercurvature being supercovariantly constant. This follows from 32 unbroken supersymmetries and allows us to prove that such vacua are exact.Comment: 16 pages, late

Adverse functions of IL‐17A in experimental sepsis

IL‐17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL‐17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL‐17A levels, which rose time‐dependently in plasma after CLP, were not affected in the absence of αβ T cells or neutrophils. In sharp contrast, γδ T cell‐knockout or γδ T cell‐depleted mice displayed baseline IL‐17A plasma levels after CLP. Neutralization of IL‐17A by two different antibodies improved sepsis (survival from ~10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti‐IL‐17A was delayed for up to 12 h after CLP. These protective effects of IL‐17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL‐17A substantially increased the production of TNF‐α, IL‐1β, and IL‐6 by these cells. These data suggest that, during experimental sepsis, γδ T cell‐derived IL‐17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL‐17A may be a potential therapeutic target in sepsis.—Flierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., Huber‐Lang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of IL‐17A in experimental sepsis. FASEB J. 22, 2198–2205 (2008)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154352/1/fsb2fj07105221.pd

Immunologic response to cryoablation of breast cancer

Purpose .With improvements in breast imaging and image-guided interventions, there is interest in ablative techniques for breast cancer. Cryosurgery initiates inflammation and leaves tumor-specific antigens intact, which may induce an anti-tumor immune response. To help define the mechanisms involved in the cryoimmunologic response, we compared cryosurgery to surgery in a murine model of breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44226/1/10549_2004_Article_3289.pd

Interleukin 13 inhibits human immunodeficiency virus type 1 production in primary blood-derived human macrophages in vitro.

The mechanisms by which cellular immunity maintains the asymptomatic state after human immunodeficiency virus type 1 (HIV-1) infection are poorly understood. CD4+ T lymphocytes play a complex role in regulating anti-HIV effector pathways, including activation of macrophages, which are themselves implicated in clinical latency and pathogenesis of symptomatic acquired immune deficiency syndrome. We have found that a newly identified T helper type 2 lymphokine, interleukin 13 (IL-13), inhibits HIV-1ADA and Ba-L replication in primary tissue culture-derived macrophages but not in peripheral blood lymphocytes. Viral production in cells was measured by viral protein (p24) and reverse transcriptase levels, while entry was assessed by proviral DNA analysis at timed intervals after infection. Inhibition by IL-13 was dose and time dependent and not mediated through altered viral entry, reverse transcription, or viral release. IL-13 is therefore a candidate cytokine for the suppression of HIV infection within monocytes and macrophages in vivo.

Study of Constrained Minimal Supersymmetry

Taking seriously phenomenological indications for supersymmetry, we have made a detailed study of unified minimal SUSY, including effects at the few percent level in a consistent fashion. We report here a general analysis without choosing a particular unification gauge group. We find that the encouraging SUSY unification results of recent years do survive the challenge of a more complete and accurate analysis. Taking into account effects at the 5-10% level leads to several improvements of previous results, and allows us to sharpen our predictions for SUSY in the light of unification. We perform a thorough study of the parameter space. The results form a well-defined basis for comparing the physics potential of different facilities. Very little of the acceptable parameter space has been excluded by LEP or FNAL so far, but a significant fraction can be covered when these accelerators are upgraded. A number of initial applications to the understanding of the SUSY spectrum, detectability of SUSY at LEP II or FNAL, BR($b\to s\gamma$), Width($Z\to b\bar b$), dark matter, etc, are included in a separate section. We formulate an approach to extracting SUSY parameters from data when superpartners are detected. For small tan(beta) or large $m_top$ both $M_half$ and $M_0$ are entirely bounded from above at O(1 tev) without having to use a fine-tuning constraint.Comment: Michigan preprint UM-TH-93-24, LaTeX, 60 pages without figures. Complete paper with inline figures available by anonymous ftp to williams.physics.lsa.umich.edu in /pub/preprints/UM-TH-93-24.ps.Z (uncompresses to 10MB / 77 pages), or by e-mailing reques