Clinical and applied immunology reviews最新文献

Data on humoral immune response against Brazilian human immunodeficiency virus type 1 (HIV-1) isolates have been collected and reviewed in reference to data published in the international literature. The results obtained up to now indicate that the Brazilian humoral immune response can be divided into at least three antibody binding serotypes: anti-Bbr, anti -B/F and anti-C/F. No neutralization serotypes have been distinguished up to now, just different degrees of resistance to neutralizing antibody (NAb), similar to data obtained by neutralization analyses of European/North American HIV-1isolates. No correlation between V3 binding antibodies, genotype and HIV-1 NAb could be observed.

Cutaneous and uveal melanoma provide excellent model systems for studying the processes of tumor progression, tumor cell invasion, metastasis and immunosurveillance. Studies that incorporate both of these models can provide novel insights into how tumor cells of common embryonic origin may respond to different environments and conditions, since cutaneous melanoma cells appear to metastasize by non-hematogenous (lymphatic) routes while uveal melanoma cells metastasize primarily through the blood. Microarray gene chip analyses have shown that aggressive cutaneous and uveal melanoma cells coexpress multiple phenotype-specific genes, which include genes previously thought specific to other cell types. These observations suggested that aggressive melanoma cells may undergo a genetic reversion to a pluripotent, embryonic-like (plastic) phenotype. Vasculogenic mimicry represents a remarkable example of tumor cell plasticity and is characterized by the unusual ability of aggressive human melanoma tumor cells to form tubular structures and patterned networks in three-dimensional culture reminiscent of embryonic vasculogenesis. Furthermore, extracellular matrices preconditioned by aggressive melanoma cells induce the aggressive, vasculogenic mimicry phenotype in poorly aggressive cells. Microarray analyses also supported previous observations that human leukocyte antigen (HLA) class I molecules are up-regulated and HLA class II molecules are down-regulated in aggressive uveal melanoma cells, which could facilitate an escape from immunosurveillance by natural killer cell activity during hematogenous metastasis. However, the up-regulation of HLA class I and down-regulation of HLA class II on the C8161 aggressive cutaneous melanoma cells compared to the poorly aggressive cutaneous melanoma cells reported in this review is contrary to previously published results for cutaneous melanoma and suggest that the aggressive cutaneous melanoma cell line could have been derived from a metastatic foci developed from a hematogenous (not lymphatic) metastasis. These observations offer unique perspectives regarding the plastic nature of aggressive melanoma cells that will continue to challenge our current thinking of identifying and targeting tumor cells that may masquerade as other cell types, yet may provide new prognostic markers for tumor detection, clinical diagnosis and novel therapeutic intervention strategies.

Clinical observations in the natural history of acquired immunodeficiency syndrome (AIDS) and other immunodeficiencies have suggested a role for certain interferon (IFN)-producing cells (originally termed NIPC) in the host defense against opportunistic infection (OI). Identification of these cells with the previously described enigmatic cells resident in thymus and T cell areas of lymphoid tissues has led to improved understanding of mechanisms of induction of Th-1 immunity. The NIPC, now referred to as plasmacytoid pre-dendritic cells or plasmacytoid dendritic cells (pDC), may carry human immunodeficiency virus (HIV)-1 from the periphery into contact with immature T cells in lymphoid tissue, leading to infection of the T cells and selective ablation of the Th-l pathway. Progressive losses of pDC numbers and function during the course of HIV infection may eventually deprive the Th-1 pathway of essential IFN-α signaling, in turn needed for an interleukin-12 (IL-12) mediated IFN-γ response. Infection of the thymus by HIV-1 is both resisted, and later probably enhanced by IFN-α locally generated by HIV-stimulated and HIV-infected pDC. The resulting thymic pathology would then lead to failure of peripheral T cell repopulation. These pDC-related processes probably contribute to the pathogenesis of AIDS and explain the original clinical observations relating the IFN-production deficit to susceptibility to OI.

The thymus is a target of human immunodeficiency virus (HIV)-1 infection in humans, and destruction of thymic progenitors and of the thymic microenvironment by HIV may preclude the generation of functional naive T cells to repopulate the peripheral CD4 T cell pool in HIV-infected people. Xenogeneic thymic grafting might provide a useful strategy for overcoming this obstacle, as xenogeneic thymi might resist HIV infection, and xenogeneic donors could provide essentially unlimited amounts of thymic tissue. We have recently demonstrated that a highly disparate (porcine) xenogeneic thymus graft can be used to replace the host thymus to reconstitute CD4⁺ T cells in thymectomized, T cell-depleted mice, and that these CD4⁺ T cells that repopulate the periphery after developing in porcine thymic xenografts are fully functional, confer resistance to opportunistic infections, and show specific tolerance to the porcine donor and the recipient. Studies in immunodeficient mice show that porcine thymic tissue is likewise capable of generating mature, functional human T cells from hematopoietic progenitors, and that these human cells are specifically tolerant of the porcine donor. Preliminary studies suggest that porcine thymic tissue may confer resistance to the destructive effects of HIV-1 infection on human thymopoiesis. Attempts to apply this approach in nonhuman primates, including simian immunodeficiency virus (SIV)-infected rhesus monkeys, have demonstrated the importance of overcoming the powerful recipient anti-pig T cell response in order to avoid rejection of porcine thymic grafts. However, preliminary results provide encouragement that a tolerant primate T cell repertoire could be generated in a porcine thymic xenograft if this initial immune response were fully prevented.

The demonstration that highly active anti-retroviral therapy (HAART) can control human immunodeficiency virus type 1 (HIV-1) viral replication and the associated destruction of the immune system provides an opportunity to implement therapeutic vaccine strategies. The Epimmune approach is based on separate vaccine immunogens designed to induce, or augment, helper T-lymphocyte (HTL) or cytotoxic T-lymphocyte (CTL) responsiveness when administered in conjunction with HAART. The vaccines are composed of carefully selected, minimal HTL or CTL epitopes. Vaccines composed of multiple epitopes can be produced and delivered using different formats, including deoxyribonucleic acid (DNA) plasmid-based vaccines and recombinant proteins.

T cell immunity is initiated by specialized antigen presenting cells known as dendritic cells (DCs). Antigen-pulsed DCs have been used to induce anti-tumor T cell and clinical responses in humans, apparently without significant toxicity. Under certain conditions, DCs even silence T cell immune responses in vivo. Therefore, DCs may be valuable tools for modulating immunity in the setting of autoimmunity, cancer, and chronic viral infections.

Since the late 1980s, when the potential for intracellular immunization using genetic methods was first suggested [1], there has been a dream that someday gene transfer methods might be available for treatment of human immunodeficiency virus (HIV)-1 infection. The goals of such gene transfer would be control of HIV-1 infection without the need for chemotherapy and the protection of the immune system from further infection with HIV-1. Thus, at the minimum, it would be expected that any functional genes expressed for this purpose would have antiviral effects sufficient to control infection and able to be expressed in T lymphocytes and macrophages targeted by HIV-1.

The pathogenesis of acquired immunodeficiency syndrome (AIDS), however, is an ongoing process in which HIV-1 infection initially alters the various tissues of the immune system, including not only T lymphocytes but also the thymus, in which T cell maturation occurs. In addition, the lymph nodes and dendritic cells, which are important for immune protection, and the bone marrow, which is essential for continued immune cell propagation are altered by HIV infection. Virus progression is undoubtedly a dynamic process, and any eventual gene therapy of HIV-1 infection that seeks to use these tissues must consider the effect that HIV has during the various periods of this progression. During a period that usually takes several years, the virus infection has a selective influence on the lymphoid compartment, reduces the available numbers of T lymphocytes, and alters their function 2, 3, 4, 5, 6. The next period of pathogenesis begins with the initiation of potent anti-retroviral therapy (ART), in which there is a selective expansion of T cells during the beginning of immune reconstitution. Here, there is an antigen-driven disproportionate stimulation of CD8 and CD4 cells that leads to an aberrant immune reconstitution due to oligoclonal expansion of cells reactive to the antigens present at the time, usually HIV-1, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [7]. Finally, there is a gradual restoration of the immune repertoire toward normalcy. It is recognized that this reconstitution varies in different persons based on residual thymic function, duration of untreated HIV-1 infection, age, and other factors, and it is not clear if this ever returns to normalcy. Thus, the lymphoid populations in most need of protection from HIV-1 often have a skewed functional capacity. In the case of stem cell gene therapy approaches, the target cells depend on a site, the marrow, which may have altered or limited supportive capacity. The issues add to the problems that must be faced in bringing gene therapy approaches to the clinic.