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Biomedical subjects

D E Mosier

Publications and source records attributed to D E Mosier.

At least 73 records · Page 4Linked to original sources
PubMed1991

Adoptive transfer of human lymphoid cells to severely immunodeficient mice: models for normal human immune function, autoimmunity, lymphomagenesis, and AIDS.

Though the development of human-to-mouse xenotransplant models is in its infancy, astonishing progress has been made in a short period of time. Two experimental applications have been developed: short-term transfer of human lymphocytes to generate models for autoimmunity and infectious diseases, and long-term engraftment of tissues with self-renewal potential. Human PBL-SCID mice have been used by multiple laboratories to study normal and autoimmune antibody responses, and have been shown to be readily infectable with HIV-1. SCID mice grafted with fetal tissue have been developed for studies of HIV-1 infection and its therapy as well as for studies of human hematopoietic cell differentiation. Human tumors appear to grow better in SCID mice than in nude mice, and hu-PBL-SCID mice can develop EBV-related B cell lymphoproliferative disease that resembles the immunoblastic lymphomas appearing in immunosuppressed transplant recipients. There is some evidence of mouse NK cells responding to the human xenograft, and of human T and B cells responding to mouse xenoantigens in these models, but these responses are not generally strong enough to have a major impact on human immune function. The use of these surrogate human models is expected to have a major impact on the understanding and treatment of human disease.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Effective therapy of the LP-BM5 murine retrovirus-induced lymphoproliferative immunodeficiency disease with diethyldithiocarbamate.

The effects of therapy with the immunomodulator diethyldithiocarbamate (DTC) on the manifestation and natural history of LP-BM5 murine retrovirus infection in adult C57 Black 6 mice was investigated. DTC itself, had limited effects on the spleen weight, serum IgM, or mitogen responses of the non-virus-infected control mice when evaluated over a 9-week period. The virus inoculum administered was such that there was approximately a twofold increase in serum IgM and a halving of phytohemagglutinin (PHA) and lipopolysaccharide (LPS) responses in about two weeks and death of all animals by about 26 weeks postinfection. Doses of DTC of 20 and 200 mg/kg weekly or 5 days per week (intraperitoneally) in mice with LP-BM5 infection did not alter the manifestations or course of the disease. Doses of 400 or 600 mg/kg given 5 days per week, starting either 2 weeks before or the day of virus inoculation significantly reduced hypergammaglobulinemia, spleen weight, lymphadenopathy, and also prolonged survival. A dose of 400 mg/kg started 2 weeks after virus inoculation resulted in partial prevention of hypergammaglobulinemia, splenomegaly, and lymphadenopathy as well as 100% survival compared with 12.5% in non-drug-treated controls at 23 weeks after virus inoculation. The 9 surviving animals in the treated group were then allocated to continue treatment or stop treatment. In the animals without further treatment, lymphadenopathy and mortality occurred starting within 6 weeks after cessation of therapy while the animals with continued treatment remained in good condition for 40 weeks. There was only a very limited and transient effect of DTC therapy on the decline of the proliferative responses to phytohemagglutinin or lipopolysaccharide in any of the treated groups in the above described experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1990

The immunoglobulin allotype contributed by peritoneal cavity B cells dominates in SCID mice reconstituted with allotype-disparate mixtures of splenic and peritoneal cavity B cells.

We have studied potential regulatory interactions between mature B lymphocyte populations by analysis of C.B-17 severe combined immunodeficient (SCID) mice reconstituted simultaneously with immunoglobulin allotype-congenic mixtures of spleen (SP) and peritoneal cavity (PerC) B cells. We have previously shown that the independent transfer of B cells from these sources leads to the long-term survival of donor B cells and reconstitution of immunoglobulin levels in SCID mice (Riggs, J.E., D.L. Robertson, R.S. Stowers, and D.E. Mosier, manuscript submitted for publication). SP and PerC B cells differ in numerous respects, with the PerC having higher proportions of large, activated B cells that express the IgM greater than IgD phenotype and greater numbers of CD5 B cells. The injection of equal numbers of B cells from SP and PerC into SCID recipients (e.g., BALB/c SP + C.B-17 Per C----SCID) has led to the following observations: (a) serum IgM allotypes in B cell chimeras revealed strict dominance by the allotype contributed by the PerC B cells; (b) this dominance was not due to regulatory T cells; (c) B cells of the unexpressed (i.e., SP) allotype were present in the chimera in the spleen but not the peritoneal cavity; and (d) immunization with TI and TD antigens failed to elicit the SP IgM allotype, whereas secondary TD antigen immunization elicited low levels of the SP IgG2a allotype. Additional experiments demonstrated concurrent expression of IgM allotypes derived from both SP and PerC B cells in recipients that: (a) received a 10-fold excess of SP B cells; (b) received SP B cells before PerC B cell transfer; or (c) received SP B cells intravenously and PerC B cells intraperitoneally. We conclude that the establishment of IgM synthesis by PerC B cells leads to a feedback inhibition of subsequent IgM synthesis by SP B cells, and that the frequency of B cells that can lead to this effect is substantially higher in peritoneal cavity than in spleen. These data provide further confirmation of regulatory interactions between B cells in the absence of T lymphocytes, but confound the interpretation of experiments supporting the existence of a separate CD5+ B cell lineage.

Animals↗
PubMed1990

Autoantibody production by severe combined immunodeficient mice reconstituted with synovial cells from rheumatoid arthritis patients.

In an attempt to characterize the heterogeneity of the human autoantibody response, mice with severe combined immunodeficiency were reconstituted with synovial or blood lymphocytes from patients with rheumatoid arthritis (RA). Mononuclear cells extracted from synovial fluid or tissue (SMC) were a greatly enriched source of IgM rheumatoid factor (RF)-producing cells compared to the peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis patients or normal donors. Six to nine weeks after reconstitution of mice with synovial mononuclear cells, 0%-39.3% (mean = 11.4%) of total IgM consisted of IgM RF compared to 0%-0.15% (mean = 0.02%) in mice given RA PBMC and 0%-1.2% (mean = 0.34%) in mice given normal PBMC. Detectable levels of IgM RF were maintained in some mice for as long as 20 weeks after transfer. Mice reconstituted with synovial membrane or synovial fluid lymphocytes produced a heterogeneous mixture of immunoglobulins. These included other autoantibodies, such as anti-nuclear and anti-cytoplasmic antibodies, and antibodies to exogenous antigens such as the Epstein-Barr virus nuclear antigen-1 (EBNA-1). This heterogeneity is further illustrated by the demonstration that the sera from mice given synovial cells also contained IgG antibodies possessing all three major VH families (VH1, VH3 and VH4) and the four major V kappa families (V kappa 1 to V kappa 4). Autoantibody production gradually decreased with time even under circumstances where total immunoglobulin levels increased, and elevated production could not be induced by antigenic stimulation. These findings describe a new model for the analysis of human autoantibody production.

Animals↗
PubMed1990

Immunodeficient mice xenografted with human lymphoid cells: new models for in vivo studies of human immunobiology and infectious diseases.

This review article deals with the transfer of human lymphoid or hematopoietic tissues to severely immunodeficient mice to create new small animal models for the study of human biology and disease. The degree of functional reconstitution in the three current models is discussed. SCID mice with human grafts have been infected with human immunodeficiency virus (HIV) to generate a small animal model for AIDS research. Epstein-Barr virus (EBV)-related lymphoproliferative disorders can also be modeled by the transfer of adult peripheral blood mononuclear cells to SCID mice.

Animals↗
PubMed1990

Biological activity of diethyldithiocarbamate (Ditiocarb, Imuthiol) in an animal model of retrovirus-induced immunodeficiency disease and in clinical trials in patients with HIV infection. The Ditiocarb Study Group.

Diethyldithiocarbamate (Ditiocarb) is a drug with diverse biological activities suggesting that it may have multiple, clinical uses. Thus, it is an inhibitor of such enzymes as cytochrome P450, it is a chelating agent for nickel and cadmium, it is a free-radical scavenger and finally, it is an immunomodulator. As such, it can restore the immune responses of immunosuppressed mice. In the murine retrovirus-induced immunodeficiency disease (LP-BM5 in C57 black 10 mice), it can prevent the development of disease when given from the day of virus inoculation until 2 weeks after virus inoculation. In addition, it can reverse disease manifestations including lymphadenopathy when started as late as 10 weeks after virus inoculation. Associated with these effects is a reduction in mortality from 100 percent to between 0 and 10 percent. When drug is stopped however, disease progression resumes. In man, Ditiocarb has been used in a series of open, non-randomized as well as randomized prospectively-controlled clinical trials in patients with HIV infection. Three randomized placebo-controlled studies have been conducted. In the largest of these, involving 389 patients, Ditiocarb was shown to be safe, non-toxic and effective. Thus, there was a 62 percent reduction in new opportunistic infections (OI) in all of the treated patients, a 50 percent reduction in ARC patients and an 82 percent reduction in AIDS patients. When new and recurrent OI and other events indicating progression were taken together, there were 17 events in 193 treated patients and 42 events in 196 placebo control patients. Statistically significant reductions in these events were seen in ARC patients, AIDS patients and all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1989

On the SCIDs?

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Animals↗
PubMed1989

Studies of HIV infection and the development of Epstein-Barr virus-related B cell lymphomas following transfer of human lymphocytes to mice with severe combined immunodeficiency.

Mice with severe combined immunodeficiency (C.B-17 scid, hereafter SCID) accept xenografts of adult human peripheral blood leukocytes (PBL). The transplanted human PBL expand in number and survive for at least thirteen months and have been shown to reconstitute human immune function at both the T and B cell levels. Human immunoglobulin production is restored, and secondary antibody responses to antigens such as tetanus toxoid can be induced. All SCID mice reconstituted with 50 x 10(6) or more PBL from donors with evidence of exposure to Epstein-Barr virus (EBV) have developed human B cell lymphomas at 8-16 weeks after PBL engraftment, whereas mice reconstituted with PBL from EBV-seronegative donors fail to develop tumors. These tumors involve both lymphatic and non-lymphatic organs, and histologically they resemble large cell or immunoblastic lymphomas. The tumors are associated with high levels of human immunoglobulin secretion and serum electrophoresis reveals oligoclonal immunoglobulin banding patterns. Analysis of tumor DNA shows the presence of EBV genomes and oligoclonal patterns of immunoglobulin JH gene rearrangement. Taken together, these observations suggest an EBV-related proliferation of B lymphocytes leading to the rapid appearance of oligoclonal B cell malignancies following transfer of B lymphocytes from "normal" donors to SCID mice. SCID mice reconstituted with PBL from EBV-seronegative donors have been infected with the LAV-1 strain of human immunodeficiency virus (HIV-1). Virus has been recovered from most infected animals by co-culture of mouse tissue with human T lymphoblasts. Some mice with high virus titers have developed an acute wasting syndrome and depletion of human T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Transfer of a functional human immune system to mice with severe combined immunodeficiency.

The pressing need for a better experimental system for AIDS research has brought into sharp focus the shortcomings of available animal models and the practical and ethical limitations of studies of immune responses and viral pathogenesis in humans. Current studies of the human immune responses are limited to relatively restrictive in vivo experiments and several in vitro systems that, although useful, allow only short-term studies and support responses to a few antigens. Neither model is particularly amenable to studies of the pathogenesis of diseases of the immune system. We report here that injection of human peripheral blood leukocytes (PBL) can result in the stable long-term reconstitution of a functional human immune system in mice with severe combined immunodeficiency (SCID). Human PBL transplanted to SCID mice increase in number and survive for at least six months; reconstituted mice show spontaneous secretion of human immunoglobulin and a specific human antibody response is induced following immunization with tetanus toxoid. All of the major cell populations present in PBL are found in the lymphoid tissue and blood of SCID recipients, although the relative proportions of B cells, T-cell subsets and monocytes/macrophages in long-term recipients differ from those found in normal PBL and, in mice transplanted with 50 x 10(6) or more PBL from Epstein-Barr virus (EBV)-seropositive donors, EBV-positive B-cell lymphomas often develop. Our results suggest that xenogeneic transplantation of human lymphoid cells into SCID mice may provide a useful model for the study of normal human immune function, the response of the immune system to pathogenic agents and early events in lymphomagensis.

Animals↗
PubMed1988

Specific H chain junctional diversity may be required for non-T15 antibodies to bind phosphorylcholine.

The secondary antibody response of mice to phosphorylcholine (PC) shows a markedly different clonal profile than the primary response. In particular, the T15 antibodies that dominate the primary response are a minor part of secondary IgG antibodies, whereas 511 and 603 antibodies become a more prominent part of the PC-specific secondary response. These three anti-PC families differ only in L chain usage. We partially sequenced the IgH chain mRNA of a series of secondary T15 and 511 hybridomas to determine the role of somatic mutation and affinity maturation in these changes in clonal profile. None of the sequenced T15 antibodies showed somatic mutations or affinity increases. In contrast, all of the 511 antibodies had extensive somatic mutation and most had significantly increased affinity for nitrophenyl-PC. The failure of T15-expressing B cells to contribute to the secondary IgG response thus is likely to be explained by their inability to undergo (or tolerate) substantial somatic mutation and affinity maturation. We also noted that all 511 antibodies sequenced by us or others had an extra amino acid encoded at the VH-D junction by either N region addition or diversity of VH-D joining. Published sequences also show a 603 family-specific change at the VH-D junction. The frequency with which these changes, which appear obligate for PC binding, occur may determine the under-representation of these clonotypes in the primary anti-PC response. The affinity maturation in 511 antibodies after somatic mutation appears to account for their expansion in the secondary response.

Amino Acid Sequence↗
PubMed1988

CD4+ T cells are required for development of a murine retrovirus-induced immunodeficiency syndrome (MAIDS).

Mice depleted in vivo of CD4+ Th cells by treatment with mAb GK1.5 were found to be resistant to the lymphoproliferative/immunodeficiency disease (MAIDS) induced in intact mice by infection with the mixture of LP-BM5 murine leukemia viruses. Depleted mice did not develop lymphadenopathy or splenomegaly, had normal serum IgM levels, normal CTL responses to alloantigens, and were able to generate PFC responses to Th-independent antigens even though frequencies of virus-producing spleen cells were comparable in depleted and intact mice. Depletion of CD4+ Th cells after infection resulted in a reversal of many abnormalities exhibited by infected controls; spleen weights, serum IgM levels, and allogeneic CTL responses of treated mice were comparable to those of uninfected controls. These results demonstrate that dysfunction of CD4+ Th cells is central to the induction and progression of both T and B cell abnormalities in MAIDS.

Animals↗
PubMed1987

Functional T lymphocytes are required for a murine retrovirus-induced immunodeficiency disease (MAIDS).

Athymic nu/nu mice were found to be resistant to the immunodeficiency disease and lethality induced in normal mice by the injection of the LP-BM5 mixture of murine retroviruses (LP-BM5 MuLV). Susceptibility to disease induction was reconstituted by injection of nu/nu mice with purified, mature T lymphocytes. The extent of viral replication of both the ecotropic and mink cell focus forming (MCF) components of LP-BM5 MuLV was equivalent in both nu/nu and normal animals. Retrovirally-induced immunodeficiency disease in mice (MAIDS) is thus dependent upon the presence of functional T lymphocytes, and high virus titers in athymic mice have little or no effect on the immune system.

Animals↗
PubMed1986

T cell activation of antigen-specific antibody responses by large B cells is MHC restricted.

The activation of small, resting B cells for antibody synthesis by helper T cells has been proposed to require an MHC-restricted interaction between the T and B cells. Large, activated B lymphocytes were, in contrast, thought to be activated by an unrestricted pathway. We re-examined this issue and found that both large and small size fractionated murine B lymphocytes required an MHC-restricted interaction with helper T cells to be activated for specific antibody synthesis. Polyspecific antibody synthesis in the same cultures was not dependent upon an MHC-restricted T-B interaction for any size category of B cell. These results are interpreted as reflecting the ability of antigen-specific B cells to focus and present antigen to T cells, in contrast to B cells of random specificity, which have no effective focusing mechanism for a given experimental antigen. We found that the polyspecific response required much higher antigen concentrations than the antigen-specific response, a result consistent with the antigen-focusing hypothesis.

Animals↗
PubMed1985

Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice.

We have shown that a mixture of murine leukemia viruses (MuLV) causes the acute onset of lymphoproliferation and immunosuppression when injected into adult C57BL/6 mice. The ecotropic/MCF (mink cell focus-inducing) mixture of MuLV stimulates polyclonal B lymphocyte proliferation and differentiation to antibody-secreting cells. Serum Ig levels are elevated for all isotypes except IgA. The viral infection leads to a rapid decline in T lymphocyte responses to mitogens and alloantigens, as well as a decrease in helper cell activity. Specific antibody responses to both T-dependent and T-independent antigens are impaired, and the response of B lymphocytes to mitogens is abolished. The profound immunosuppression seems to be due to the MuLV-induced polyclonal activation of lymphocytes. No active suppression of normal lymphocyte responses by cells from virus-infected mice was observed. The disease induced by the LP-BM5 MuLV isolate thus seems a promising model for the study of lymphocyte activation and the mechanisms of retrovirus-induced immunosuppression.

Acute Disease↗