Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BB rat is among the best models of insulin-dependent diabetes mellitus--with onset and pathogenesis closely resembling the human disease. One unusual feature is a severe T-cell lymphopenia, which appears to be inherited as a recessive trait controlled by a single gene, Lyp. Based on genetic analysis of several crosses, we show that development of diabetes involves at least three genes: Lyp, which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, a gene linked to the major histocompatibility complex (MHC) on chromosome 20, and a third unmapped gene for which the Fischer rat strain carries an allele conferring resistance.
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PMID:Genetic dissection of autoimmune type I diabetes in the BB rat. 130 51

Molecules encoded by the major histocompatibility complex (MHC) are crucial for the proper functioning of the immune response. In this study, the levels of class I and class II major histocompatibility antigens on lymphocytes from strain A mice were measured as a function of age. Class I protein levels increased significantly on both peripheral blood and spleen (T cells and B cells) lymphocytes with age. This increase in MHC class I protein levels was accompanied by an increase in class I mRNA levels. On the other hand, class II protein levels did not show a significant change with age. Moreover, while the percentage of class I-expressing spleen lymphocytes stayed at a steady-state level of 100% with age, the percentage of class II-expressing spleen lymphocytes decreased from 85% in young animals to 70% in old animals. This decrease was due to a decrease in the relative proportion of B cells compared to T cells in the spleen lymphocyte population of old mice. When class II mRNA levels were measured, it was found that these levels decreased markedly with age. Overall, it is clear that the regulation of MHC class I and class II expression changes with age in A strain mice. Since optimal levels of MHC expression are crucial for the proper functioning of cellular and humoral immune responses, it will be most interesting to understand how the control of MHC gene expression changes with age and whether MHC gene expression can be modulated in old individuals to restore better immune function.
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PMID:Major histocompatibility complex antigen expression on lymphocytes from aging strain A mice. 186 85

Lymphocytes from diabetes-prone Biobreeding rats consistently fail to generate T-cell-mediated cytotoxicity under conditions where cytotoxic T lymphocyte activity is readily demonstrated in normal rats. The failure is associated with generalized T-cell lymphopenia and marked reduction in the frequency of CD8+ cells. The few remaining CD8+ cells are widely held to be natural killer cells rather than class I major histocompatibility complex-restricted T lymphocytes. In this report we show that a detectable percentage of CD8+ lymphocytes express the T-cell receptor for antigen, thus identifying them as part of the T-cell lineage. The failure of these CD8+ T-cell-receptor-positive T cells to lyse target cells that are susceptible to T-cell mediated cytotoxicity is associated with markedly reduced expression of cell-surface CD8. Targets expressing higher than normal levels of class I major histocompatibility complex target antigen could be lysed, suggesting that reduction in CD8 has decreased T-cell activity for target antigen. We discuss the derivation of T cells that express low levels of CD8 and the role they could play in generating autoimmune diabetes.
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PMID:Cytotoxic T-cell precursors with low-level CD8 in the diabetes-prone Biobreeding rat: implications for generation of an autoimmune T-cell repertoire. 210 82

Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.
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PMID:Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy. 280 69

Injection of major histocompatibility complex (MHC)-compatible bone marrow cells from normal animals into neonatal BB rats resulted in a striking decrease in incidence of diabetes and restoration of concanavalin A (ConA) and mixed lymphocyte responses. However, injection of bone marrow cells pretreated with anti-rat thymocyte antiserum plus complement to remove mature T cells had no effect on incidence of disease, suggesting that mature T cells in the bone marrow inoculum were responsible for prevention of diabetes. Because the decreased incidence of diabetes in rats injected with untreated bone marrow appeared to be unrelated to the extent of lymphopenia in these animals, the involvement of T cells in the onset of diabetes must reflect a defect in the normal function of these cells rather than their absolute number. Approximately 50% of the W3/13+ cells in the spleens of BB rats lacked the OX-8 and W3/25 T cell subset markers. The identity of this W3/13+, OX-8-, W3/25- blank subset remains to be established. Our results, interpreted in light of studies from the other laboratories, suggest the existence of multiple abnormalities in the BB rat, including the presence of T cells as effector or helper cells that augment onset of disease and the absence of a regulatory T cell circuit that could prevent the disease.
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PMID:Prevention of diabetes in BB rats. I. Evidence suggesting a requirement for mature T cells in bone marrow inoculum of neonatally injected rats. 294 18

Development of cell-mediated immunity in young ruminants appears to be under the influence of the thymus. In sheep, prenatal removal of the thymus has little effect on postnatal growth of lambs. However, lambs are immunodeficient compared with normal controls, and they exhibit depressed delayed hypersensitive skin responses to antigens such as tuberculin purified protein derivative. Lymphopenia accompanying the immunodeficiency appears to be due to depletion of a particular population of T-cells (thymus derived) that have reduced response to mitogens and decreased numbers as the lamb matures. Young lambs are less responsive than adult sheep to vaccination with irradiated Trichostrongylus colubriformis larvae. The basis of this lowered responsiveness appears to be not only the immaturity of the cell-mediated immune response but also the segregation of the lambs into high and low responders. This immune responsiveness is possibly under the genetic control of the ovine major histocompatibility complex. It may be possible to select and breed sheep and cattle for responsiveness to vaccination against parasitic, viral, and bacterial diseases.
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PMID:Development of cell-mediated immunity in young ruminants. 388 81

We have studied the occurrence of two phenotypic components (pancreatic lymphocytic infiltration [PLI] of the pancreas and T lymphocytopenia) of the spontaneous insulin-dependent diabetic syndrome (IDDM) in the progeny of hybrids obtained by crossing BB diabetic rats with rats of inbred strains differing from the BB rat at the major histocompatibility complex, RT1. Both PLI and T lymphopenia were seen in animals with all three possible genotypes in both (BUF x BB) and (LEW x BB) lines. PLI was seen in all IDDM animals. T lymphopenia was strongly associated with overt IDDM in both lines (chi 2 = 22.28, p = 0.00002 and chi 2 = 19.28, p less than 0.00001). In addition, T lymphopenia was associated with PLI with and without IDDM in both lines (chi 2 = 8.32, p = 0.0039 an chi 2 = 3.95, p = 0.0467). Not all animals exhibiting PLI without overt IDDM had depressed T cells. Not all animals with T lymphopenia had PLI with or without IDDM. In both lines, the overt IDDM occurred only in animals with at least one RT1 u haplotype derived from the BB rat, confirming our previously reported association of IDDM and RT1. We interpret this evidence to suggest that the overt IDDM syndrome requires one MHC-linked gene and at least two non-MHC-linked genes, which determine susceptibility to PLI and to circulating T lymphocyte depression.
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PMID:Spontaneous diabetes mellitus syndrome in the rat. II. T lymphopenia and its association with clinical disease and pancreatic lymphocytic infiltration. 633 14

We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4-Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor-derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4-Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.
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PMID:In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. 751 23

The BB/Wor rat develops spontaneous autoimmune diabetes mellitus and also frequently develops lymphocytic thyroiditis. To clarify the role of T cell lymphopenia and the major histocompatibility complex (MHC) in the development of these autoimmune disorders, we studied back-cross animals between the inbred thyroiditis and diabetes-prone BBNB/Wor subline (MHC RT1.AuBuDuCu) and three nonlymphopenic MHC-congenic rat strains: PVG.RT.1u (RT1.AuBuDuCu), PVG.R8 (RT1.AaBuDuCu), and PVG.R23 (RT1.AuBaDaCav1). We observed that 1) lymphopenia is absolutely required for the development of spontaneous diabetes and insulitis, and is usually associated with the development of thyroiditis; 2) the MHC region to the right of the class I RT1.A locus is strongly correlated with diabetes and insulitis; and 3) this region is also significantly associated with the development of thyroiditis, but the susceptibility of certain MHC class II alleles (u and a) for disease development is distinct for insulitis and thyroiditis. Furthermore, no recombination was observed between lymphopenia (lyp) and the neuropeptide Y (Npy) gene polymorphism, which confirmed that lyp maps very close to Npy. The present data suggest that spontaneous insulitis and thyroiditis in the BB/Wor rat develop through common immune defects involving T cell lymphopenia, but do not always segregate together due to disease-specific interactions with the MHC class II-linked genes.
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PMID:Genetics of the BB rat: association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II. 758 30

The development of insulin-dependent diabetes mellitus in the BB rat requires the presence of the class II major histocompatibility complex alleles of the RT1u haplotype and a T cell lymphopenia. The lymphopenia gene (lyp) behaves as an autosomal recessive trait that co-segregates with markers of rat chromosome 4. The current study examines two congenic and four recombinant inbred rat strains derived from BB and Buffalo rat strains using markers for simple-sequence length polymorphisms to confirm the linkage of the lymphopenia gene to chromosome 4. In two of these lines the lymphopenia associates with a recombinant haplotype that is BB-like at the D4Mit6 marker and Buffalo-like at D4Mit7 (neuropeptide Y locus) thus placing the lyp locus between these two closely linked markers.
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PMID:Recombinant haplotype bearing the lymphopenia gene of the BB rat. 771 Jul 64


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