Immune surveillance against a solid tumor fails because of immunological ignorance.
(1/1529)
Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, overall immune surveillance against such tumors seems relatively inefficient. We studied immune surveillance against a s.c. sarcoma expressing a characterized viral tumor antigen. Surprisingly, the tumor cells were capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they were transplanted as small tumor pieces, tumors readily grew. Tumor growth correlated strictly with (i) failure of tumor cells to reach the draining lymph nodes and (ii) absence of primed cytotoxic T cells. Cytotoxic T cells were not tolerant or deleted because a tumor antigen-specific cytotoxic T cell response was readily induced in lymphoid tissue by immunization with virus or with tumor cells even in the presence of large tumors. Established tumors were rejected by vaccine-induced effector T cells if effector T cells were maintained by prolonged or repetitive vaccination, but not by single-dose vaccination. Thus, in addition to several other tumor-promoting parameters, some antigenic peripheral sarcomas-and probably carcinomas-may grow not because they anergize or tolerize tumor-specific T cells, but because such tumors are immunologically dealt with as if they were in a so-called immunologically privileged site and are ignored for too long. (+info)
Availability of immune globulin intravenous for treatment of immune deficient patients--United States, 1997-1998.
(2/1529)
Immune globulin intravenous (IGIV) is a lifesaving treatment for patients with primary immunodeficiency. Since November 1997, a shortage of IGIV has existed in the United States. In 1998, the Food and Drug Administration (FDA) required pharmaceutical companies to increase the frequency of reporting on IGIV distribution from biannually to monthly; in addition, FDA facilitated IGIV distribution and informed clinicians about the ongoing shortage. To assess the impact of the IGIV shortage on patient care, in 1998 the Immune Deficiency Foundation (IDF) surveyed physicians caring for immunodeficient patients about whether they have had difficulty obtaining IGIV, measures they have taken because of the shortage, and the effect of the shortage on their patients. This report summarizes data reported to FDA and data obtained from the IDF survey and provides recommendations for IGIV use during the shortage. (+info)
Management of primary antibody deficiency by consultant immunologists in the United Kingdom: a paradigm for other rare diseases.
(3/1529)
Variation in clinical practice and its effect on outcome is little known for rare diseases such as primary antibody deficiency. As part of a national audit a survey of all 30 consultant immunologists in the United Kingdom dealing with primary antibody deficiency syndromes in adults and children was carried out in 1993 to ascertain their practices in diagnosis and management. Consensus guidelines were published after the survey was completed. Comparison of the survey results of clinical practice at the time the guidelines were published with the standards identified highlighted that the practice of a minority of specialists was at variance with their peers and with the consensus document, particularly in the use of intramuscular immunoglobulin, the dose and frequency of intravenous immunoglobulin, and target trough immunoglobulin G concentration, which has implications for the quality of patient care. However, much closer agreement existed in the key areas of management, such as diagnosis and selection of intravenous immunoglobulin. The approach and the problems identified are relevant to the management of other rare diseases, in which diagnosis and management is complex and there are few specialists with the necessary knowledge to undertake such care. This survey, the first attempted audit of practice, shows that within a motivated group of specialists highly significant differences in practice may exist and the authors emphasise the importance of setting clear guidelines against which care can be assessed. (+info)
Pesticides and immunosuppression: the risks to public health.
(4/1529)
There is substantial experimental, epidemiological and other evidence that many pesticides in widespread use around the world are immunosuppressive. This poses a potentially serious health risk in populations highly exposed to infectious and parasitic diseases, subject to malnutrition, and inadequately serve by curative health programmes. An expanded programme of research is needed to investigate this potential risk and to design precautionary measures. (+info)
Immunodeficiency syndrome in a 3-year-old llama.
(5/1529)
An adult, castrated male llama was presented for evaluation of a chronic respiratory problem. Complete blood analyses indicated a leukopenia and hypoproteinemia. Radial immunodiffusion, bone marrow core, and lymph node biopsies supported a tentative diagnosis of juvenile llama immunodeficiency syndrome. This diagnosis was confirmed by postmortem findings. (+info)
Accelerated emigration of B lymphocytes in the Xid mouse.
(6/1529)
The B cell receptor is required for the emigration of newly generated B lymphocytes and for their maintenance in the periphery. A specific maintenance defect was noted in fraction I (IgDhighIgMlow) B cells in Xid mice (which harbor a mutation in Btk). Although Bcl-2 levels in fractions I and II (IgDhighIgMhigh) are equivalent in normal and Xid B cells, a novel peak of Bcl-2low fraction III (IgDlowIgMhigh) B cells was noted in the Xid mouse. Since this B cell population resembled bone marrow immature B cells, we examined the emigration of newly formed B cells in normal and Xid mice. These studies revealed the accelerated emigration of newly formed Xid B cells. We conclude that distinct Btk-independent and Btk-dependent signals mediate emigration and maintenance events during peripheral B cell maturation. (+info)
Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase.
(7/1529)
Bruton's tyrosine kinase (Btk) plays a critical role in B cell Ag receptor (BCR) signaling, as indicated by the X-linked immunodeficiency and X-linked agammaglobulinemia phenotypes of mice and men that express mutant forms of the kinase. Although Btk activity can be regulated by Src-family and Syk tyrosine kinases, and perhaps by phosphatidylinositol 3,4,5-trisphosphate, BCR-coupled signaling pathways leading to Btk activation are poorly understood. In view of previous findings that CD19 is involved in BCR-mediated phosphatidylinositol 3-kinase (PI3-K) activation, we assessed its role in Btk activation. Using a CD19 reconstituted myeloma model and CD19 gene-ablated animals we found that BCR-mediated Btk activation and phosphorylation are dependent on the expression of CD19, while BCR-mediated activation of Lyn and Syk is not. Wortmannin preincubation inhibited the BCR-mediated activation and phosphorylation of Btk. Btk activation was not rescued in the myeloma by expression of a CD19 mutant in which tyrosine residues previously shown to mediate CD19 interaction with PI3-K, Y484 and Y515, were changed to phenylalanine. Taken together, the data presented indicate that BCR aggregation-driven CD19 phosphorylation functions to promote Btk activation via recruitment and activation of PI3-K. Resultant phosphatidylinositol 3,4,5-trisphosphate probably functions to localize Btk for subsequent phosphorylation and activation by Src and Syk family kinases. (+info)
Glutamate augments retrovirus-induced immunodeficiency through chronic stimulation of the hypothalamic-pituitary- adrenal axis.
(8/1529)
The mechanisms for activating the hypothalamic-pituitary-adrenal (HPA) axis and the roles glucocorticoids play in the pathogenesis of chronic infectious disease are largely undefined. Using the LP-BM5 model of retrovirus-induced immunodeficiency, we found alterations in HPA axis function, manifested as an increase in circulating levels of adrenocorticotropic hormone and corticosterone, beginning after only 3 mo of infection. These changes occurred contemporaneously with a shift in the profile of circulating cytokines from a Th1-dominant (IFN-gamma) to Th2-dominant (IL-4, IL-10) phenotype. No significant changes in either circulating IL-1beta, IL-6, or TNF-alpha levels were observed in infected mice. Administering the N-methyl-D-aspartate receptor antagonist MK-801 to infected mice normalized plasma adrenocorticotropic hormone and corticosterone levels, indicating that glutamate was a major activator of the HPA axis. Moreover, MK-801 treatment of late-stage mice also reversed the type 1 to type 2 cytokine shift to a degree comparable or superior to treatment with the glucocorticoid receptor antagonist RU-486. These findings indicate that HPA axis activation during LP-BM5 retrovirus infection is mediated by the chronic hyperactivation of glutamatergic pathways in the hypothalamus. Through this mechanism, the degree of peripheral immunodeficiency observed in the late-stage disease is profoundly augmented. (+info)