Clinical and applied immunology reviews最新文献

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. Activation of the complement system plays a fundamental role in the pathogenesis of SLE. For the past several decades, laboratory monitoring of SLE has focused primarily on measurement of serum C3, C4, and their activation products. However, the utility of these measures as biomarkers for diagnosis and assessment of disease activity of SLE is still debated. Over the same time span, knowledge of the complement system has advanced remarkably, with more than 30 proteins identified. In view of the urgent need for identifying reliable lupus biomarkers, it is appropriate to revisit the issue of whether the complement system is a potential source of biomarkers for SLE. This article will review historical aspects of complement measurement in SLE, and summarize recent advances that may lead to a newly rejuvenated “gold rush” to mine the complement system for biomarkers of SLE. Specifically, development and utility of a novel assay that measures cell-bound complement activation products as lupus biomarkers will be discussed.

Even after matching the alleles for the major histocompatibility complexes (MHC), grafts are rejected in a considerable percentage of transplant recipients by the host immune system. In these patients, the host T cells recognize unique antigenic peptides on the cells from the transplanted grafts. These peptides are different from that of hosts due to non-MHC polymorphic differences between the host and the donor. To distinguish between the MHC and these, they were termed minor histocompatibility (mH) complexes. Thus, mH antigens (mH-Ags) are historically defined as allo-peptides derived from allelic gene products that are capable of eliciting T cell responses. Because of their significance in determining the clinical outcome of graft acceptance and graft-versus-host disease (GvHD), mH-Ags have been intensively studied for decades. Also, a strong T cell mediated immune response to mH antigenic peptides has the potential for formulating adoptive cellular immunotherapy for patients with hematological malignancies (Graft-versus-Leukemia, GvL). Utilizing recent technological advances the identities of many human and murine mH antigenic peptides have been defined towards achieving clinical applications. These antigenic peptides are currently being evaluated in clinical or basic immunological studies for their ability to produce effective T cell responses. Furthermore, to our surprise recent studies have revealed that some of the full-length mH proteins-themselves may possess specialized immune functions. This novel discovery is dictating a paradigm shift to redefine the functionality of mH-Ags. Given that the novel immune regulatory functions of mH-Ags can also be harnessed; the possibilities to formulate additional cancer immunotherapies are expanding.

Acute leukemia patients who relapse after haematopoetic stem cell transplantation (HSCT) have poor prognosis with few therapeutic options. An immunotherapeutic approach that specifically targets the leukemia to treat and prevent these relapses could improve survival rates for these patients. Recently a number of potential antigenic targets for leukemia have been described. These include over-expressed normal antigens such as survivin, leukemia-specific targets resulting from translocations and mutations and hematopoietic-restricted minor histocompatibility antigens such as HA-1 and HA-2. Considerable experimental data indicates that cytotoxic T cells targeting these antigens can be generated in vitro. Further improvements in the efficacy of antigen presentation and T cell activation and expansion will facilitate the clinical application of these T cells as a therapeutic strategy for patients who are likely to relapse after HSCT.

The immunotherapy of patients with metastatic melanoma is currently at a crossroads. Indeed, recent results from vaccine strategies worldwide have revealed a strikingly low overall response rate in patients with stage IV melanoma. Although disappointing, we have gained valuable insight and knowledge about how vaccines interact with the host immune response and to melanoma. However, although an immunological response to therapy is often reported from various clinical trials, it does not contribute to a patient's long term survival. It has been proven time and again that an immunological response to therapy does not necessarily translate into a meaningful clinical response. This frustrating dichotomy of response continues to vex investigators, providing a glaring example of our poor understanding of the immunologic response to cancer. Thus, we remain at the crossroads of understanding and treatment. On the one hand, we have dramatically advanced the field of tumor immunology/immunotherapy over the last 20 years. On the other hand, we have made little headway in truly developing effective treatment options for patients with stage IV disease. We must realize our previous shortcomings and failures in order to learn from them and develop improved therapies. The future of immunotherapy remains a bright ray of hope for everyone, with the road to success paved with the previous hard work of thousands of clinicians and researchers everywhere. Towards this end, this review hopes to provide the reader with the current state of affairs for the immunotherapy of melanoma as well as a primer of where we might be heading in the future.

As the incidence of myelodysplastic syndromes (MDS) increases with the ageing of the population, new and promising therapeutic approaches are being developed. “Proper application of such new strategies relies on a thorough diagnosis of these variable and pleiomorphic disorders. Cytology and cytogenetics are included in the stratification of MDS, and are the main classification criteria in two successive systems. However, the progress of multiparametric immunophenotyping and flow cytometry techniques suggest that this approach may soon become an inclusive part of the diagnostic criteria of MDS. In this review of the literature, the features of MDS and the evolution of the classification these disorders is first summarized. An extensive analysis of flow cytometry approaches, especially multiparametric, is then presented, comparing the various strategies and their output.

Current information regarding immunophenotyping of MDS indicates that several anomalies in the expression of leukocyte differentiation antigens are invaluable for their diagnosis and prognosis. A more thorough and standardized comparison between normal bone marrow and MDS samples, including pattern evaluation rather than as subset enumeration, should soon further provide an efficient tool for the definition and outcome prediction of these diseases. The diagnosis of myelodysplastic disorders (MDS) currently relies on cytological features and karyotypic anomalies. These methods allow using current classifications to discriminate between the various forms of MDS. A review of the literature demonstrates that the past 5 years have seen increasing information regarding multiparametric immunophenotyping of MDS bone marrow by flow cytometry. These approaches, once standardized, should provide an additional valuable tool for the diagnosis and management of MDS patients.

Over the last decade there have been some profound changes in the way we treat inflammatory arthritis. In the late 1980's and early 1990's, a significant philosophy change that had been underway for at least a decade was formalized with the concept of “inverting the pyramid”, which was to treat patients early and aggressively to prevent joint damage. In the late 1990's the biologic agents became available and these played into this concept of early aggressive therapy with their ability to affect inflammation rapidly and prevent joint damage. Currently the use of the biologic agents is undergoing some “fine tuning” as we add their power to older disease modifying agents such as methotrexate. New biologic agents are on the horizon that will hopefully add to the ability to diminish the impact of inflammatory arthritis. Cost and unknown long-term side effects add caution to the use of these agents. Rheumatologists finally have therapies that we do not need statisticians to tell us that they work; our patients demonstrate their efficacy to us daily.

The rapid spread of West Nile Virus (WNV) across the North American continent has led to a need to understand what assays for WNV antibodies are available and how they are used as diagnostic and epidemiologic tools. In this article, we review six methods for measuring WNV antibodies in human serum, plasma, and cerebrospinal fluid. The complement fixation and hemagglutination inhibition assays were historically important; however, due to their low sensitivity, low specificity, and complex technical and reagent production issues, they are no longer in common use. The plaque reduction neutralization test is the gold standard for WNV antibody detection; due to its complexity and long turnaround time, however, it is increasingly reserved for establishing the presence of WNV infection in a geographic area and characterizing problematic samples. The immunofluorescence assay measures both IgG and IgM antibodies to WNV. Although historically considered insensitive, recent studies using commercially available slides have shown acceptable performance; the immunofluorescence assay is thus a cost-effective way to measure WNV antibodies in laboratories that routinely test small numbers of samples. The enzyme-linked immunosorbent assay (ELISA) format is the most popular method currently used to detect WNV IgG and IgM. Both indirect and monoclonal antibody-mediated antigen capture formats of IgG ELISAs have been described, whereas nearly all IgM ELISAs utilize the IgM capture format. Before 2000, WNV antibody ELISAs employed native WNV antigens; since then, there has been a dramatic shift toward using recombinant WNV antigens, particularly subviral particles containing the envelope protein. Like in the other assays mentioned, however, antibodies induced by other flavivirus infections may crossreact with both native and recombinant WNV antigens, necessitating concurrent measurement of antibodies to flaviviruses endemic in a given geographic area. The new microsphere immunoassay shows great promise as a sensitive, specific, and cost-effective method for simultaneously measuring antibodies to multiple flaviviruses. This method has also been used to characterize antibodies to nonstructural WNV proteins; these antibodies appear to be highly specific for WNV, and their measurement may soon be the test of choice for diagnosing WNV infection.

Viral diseases continue to pose some of the greatest challenges to modern medicine. For many viral diseases, prophylactic vaccines are unlikely to be developed in the near future. Fortunately, effective antiviral therapies have been developed for many of these viruses. In this review, I will focus on antiviral therapy for herpes simplex virus, human immunodeficiency virus, hepatitis C virus, and human papillomavirus. The development of compounds targeting these viruses illustrates many of the principles driving current antiviral development. It is likely that our increasing understanding of viral replication and the virus-host interaction will lead to more rapid development of new antivirals in the future.