DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes

Optimal HIV vaccines should elicit CD8+ T cells specific for HIV proteins presented on MHC class I products, because these T cells contribute to host resistance to viruses. We had previously found that the targeting of antigen to dendritic cells (DCs) in mice efficiently induces CD8+ T cell responses. To extend this finding to humans, we introduced the HIV p24 gag protein into a mAb that targets DEC-205/CD205, an endocytic receptor of DCs. We then assessed cross-presentation, which is the processing of nonreplicating internalized antigen onto MHC class I for recognition by CD8+ T cells. Low doses of αDEC-gag, but not control Ig-gag, stimulated proliferation and IFN-γ production by CD8+ T cells isolated from the blood of HIV-infected donors. αCD205 fusion mAb was more effective for cross-presentation than αD209/DC-SIGN, another abundant DC uptake receptor. Presentation was diverse, because we identified eight different gag peptides that were recognized via DEC-205 in 11 individuals studied consecutively. Our results, based on humans with highly polymorphic MHC products, reveal that DCs and DEC-205 can cross-present several different peptides from a single protein. Because of the consistency in eliciting CD8 + T cell responses, these data support the testing of αDEC-205 fusion mAb as a protein-based vaccine

A miniaturized mW thermoelectric generator for nw objectives: continuous, autonomous, reliable power for decades.

We have built and tested a miniaturized, thermoelectric power source that can provide in excess of 450 {micro}W of power in a system size of 4.3cc, for a power density of 107 {micro}W/cc, which is denser than any system of this size previously reported. The system operates on 150mW of thermal input, which for this system was simulated with a resistive heater, but in application would be provided by a 0.4g source of {sup 238}Pu located at the center of the device. Output power from this device, while optimized for efficiency, was not optimized for form of the power output, and so the maximum power was delivered at only 41mV. An upconverter to 2.7V was developed concurrently with the power source to bring the voltage up to a usable level for microelectronics

Lichen planus in two immunodeficient hosts

The exact pathogenic mechanism involved in lichen planus (LP) remains obscure. Two patients who have severe immunodeficiency diseases and who developed LP during the course of their illness are reported here. Both patients had hypogammaglobulinemia and disturbed immune function prior to the development of LP. Although such an association could be coincidental, the development of LP may be related to the underlying immune disturbances. Association of LP with several other disorders of the immune system has been previously observed. Other evidence for the possible involvement of an immunopathogenic mechanism in LP includes (1) deposition of immunoglobulin within the colloid bodies and at the dermoepidermal junction, (2) predominantly T cell dermal infiltrate in LP lesions, and (3) existence of clinical and histologic similarities between graft-versus-host disease and LP

Natural killer cell function and interferon generation in patients with primary immunodeficiencies

Patients with primary immunodeficiency disorders were evaluated for three aspects of natural defense: natural killer (NK) cells which lyse HSV-infected fibroblasts [NK(HSV-FS)], NK cells which lyse K562 tumor targets [NK(K562)], and interferon-α generation. In addition, capacity to make interferon upon challenge with other commonly used inducers was also evaluated. Most patients with severe combined immunodeficiency disease (SCID) and deficits of both T- and B-cell function demonstrated normal NK function with one or both targets. Six of eight SCID patients generated interferon-α at or below the lower limit of normal while only two made clearly normal levels. Six of 10 patients with Wiskott-Aldrich syndrome (WAS) had normal NK(K562) and five of 10 generated normal levels of interferon-α but all had severely deficient NK(HSV-FS). Patients with Bruton's agammaglobulinemia demonstrated normal NK and interferon generation, as did patients with common variable immunodeficiency, even when subdivided into patients with T-cell proliferative deficiencies and those with only hypogammaglobulinemia. Natural defense parameters may help categorize patients with SCID and WAS and help define these heterogeneous diseases

Effects of exogenous interferon in cytomegalovirus infections complicating bone marrow transplantation

Human leukocyte interferon was administered to two patients with cytomegalovirus infection which developed following allogeneic bone marrow transplantation. In one patient with hepatitis and evidence of concurrent graft-vs-host disease, significant clinical improvement and disappearance of viremia was observed. Interferon therapy was associated with suppression of lymphocyte responses to mitogens and, in one case, with a decrease of complement-fixing antibody titers to cytomegalovirus. Other immunologic parameters were unchanged. No suppression of marrow engraftment was observed

Reconstitution in Severe Combined Immunodeficiency by Transplantation of Marrow from an Unrelated Donor

A patient with severe combined immunodeficiency received seven transplants of bone marrow from an HLA-B-compatible and HLA-D-compatible unrelated donor in an attempt to provide immunologic reconstitution. The first four transplants achieved restricted engraftment with evidence of rudimentary immunologic function. A fifth transplant, given after low-dose cyclophosphamide, produced reconstitution of cell-mediated immunity. Marrow aplasia developed after recontamination with a non-pathogenic microflora. Transplantation of marrow previously stored in liquid nitrogen was ineffective. A subsequent transplant, administered after high-dose cyclophosphamide, achieved durable engraftment, with complete hematopoietic and immunologic reconstitution. Seventeen months after transplantation, full functional engraftment persists. Graft-versus-host disease has been chronic and moderately severe, but limited to the skin and oral mucosa. Transplantation of marrow from unrelated histocompatible donors may provide a useful treatment for patients with severe combined immunodeficiency or aplastic anemia who lack a matched sibling or related donor. (N Engl J Med 297:1311–1318, 1977) A MAJOR obstacle to the general application of bone-marrow transplantation is that the majority of the patients afflicted with the lethal disorders for which this approach is indicated will lack a histocompatible sibling donor. 1 , 2 The probability that any one sibling will be HLA genotypically identical to the patient is only one in four. If, however, histocompatible unrelated persons could be used as marrow-transplant donors, this therapeutic approach would be available to a larger number of patients. We here report the successful immunologic and hematologic reconstitution of a child with severe combined immunodeficiency and secondary marrow aplasia by transplantation of marrow . . 

Immunologic Profile of Highly Exposed Yet HIV Type 1-Seronegative Men

The host immune factors that determine susceptibility to HIV-1 infection are poorly understood. We compared multiple immunologic parameters in three groups of HIV-1-seronegative men: 14 highly exposed (HR10), 7 previously reported possibly to have sustained transient infection (PTI), and a control group of 14 low risk blood bank donors (BB). Virus-specific cellular immune assays were performed for CD4+ T helper cell responses, CD8+cytotoxic T lymphocyte activity, CD8+ cell chemokine release, and CD8+ cell-derived antiviral soluble factor activity. General immune parameters evaluated included CCR5 genotype and phenotype, interferon α production by PBMCs, leukocyte subset analysis, and detailed T lymphocyte phenotyping. Comparisons revealed no detectable group-specific differences in measures of virus-specific immunity. However, the HR10 group differed from the BB group in several general immune parameters, having higher absolute monocyte counts, higher absolute CD8+ T cell counts and percentages, lower naive and higher terminal effector CD8+ cells, and lower levels of CD28+CD8+cells. These changes were not associated with seropositivity for other chronic viral infections. The PTI men appeared to have normal levels of monocytes and slightly elevated levels of CD8+ T cells (also with increased effector and decreased naive cells). Although we cannot entirely exclude the contribution of other chronic viral infections, these findings suggest that long-lived systemic cellular antiviral immunity as detected by our assays is not a common mechanism for resistance to infection, and that resistance may be multifactorial. General immune parameters reflected by CD8+ T cell levels and activation, and monocyte concentrations may affect the risk of infection with HIV-1, and/or serve as markers of exposure