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Biomedical subjects

L Muul

Publications and source records attributed to L Muul.

10 recordsLinked to original sources
PubMed2000

Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model.

Host immune responses against foreign transgenes may be a major obstacle to successful gene therapy. To clarify the impact of an immune response to foreign transgene products on the survival of genetically modified cells, we studied the in vivo persistence of cells transduced with a vector expressing a foreign transgene compared to cells transduced with a nonexpressing vector in the clinically predictive rhesus macaque model. We constructed retroviral vectors containing the neomycin phosphotransferase gene (neo) sequences modified to prevent protein expression (nonexpressing vectors). Rhesus monkey lymphocytes or hematopoietic stem cells (HSCs) were transduced with nonexpressing and neo-expressing vectors followed by reinfusion, and their in vivo persistence was studied. While lymphocytes transduced with a nonexpressing vector could be detected for more than 1 year, lymphocytes transduced with a neo-expressing vector were no longer detectable within several weeks of infusion. However, five of six animals transplanted with HSCs transduced with nonexpression or neo-expression vectors, and progeny lymphocytes marked with either vector persisted for more than 2 years. Furthermore, in recipients of transduced HSCs, infusion of mature lymphocytes transduced with a second neo-expressing vector did not result in elimination of the transduced lymphocytes. Our data show that introduction of a xenogeneic gene via HSCs induces tolerance to the foreign gene products. HSC gene therapy is therefore suitable for clinical applications where long-term expression of a therapeutic or foreign gene is required.

Animals↗
PubMed1998

T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates.

Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for gene-corrected T lymphocytes, which may overcome inefficient gene transfer. Four years after three newborns with this disease were given infusions of transduced autologous umbilical cord blood CD34+ cells, the frequency of gene-containing T lymphocytes has risen to 1-10%, whereas the frequencies of other hematopoietic and lymphoid cells containing the gene remain at 0.01-0.1%. Cessation of polyethylene glycol-conjugated adenosine deaminase enzyme replacement in one subject led to a decline in immune function, despite the persistence of gene-containing T lymphocytes. Thus, despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect.

Adenosine Deaminase↗
PubMed1998

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

Adult↗
PubMed1995

T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years.

In 1990, a clinical trial was started using retroviral-mediated transfer of the adenosine deaminase (ADA) gene into the T cells of two children with severe combined immunodeficiency (ADA- SCID). The number of blood T cells normalized as did many cellular and humoral immune responses. Gene treatment ended after 2 years, but integrated vector and ADA gene expression in T cells persisted. Although many components remain to be perfected, it is concluded here that gene therapy can be a safe and effective addition to treatment for some patients with this severe immunodeficiency disease.

Adenosine Deaminase↗
PubMed1980

Neoplasms of immunoregulatory T cells in clinical investigation.

Normal T cells play a critical role in the regulation of humoral immune responses by acting as potentiators (helper cells) or inhibitors (suppressor cells) of the process by which B cells differentiate into immunoglobulin-secreting plasma cells. Certain diseases in which malignant T cells appear to retain an immunoregulatory function are characterized by a propensity of a lymphomatous T-cell population to infiltrate skin. Some cutaneous T-cell lymphomas, as well as some T-cell neoplasms without dermatologic involvement, provide a homogeneous supply of T lymphocytes which act as immunoregulators. The availability of neoplastic T cells with immunoregulatory properties could accelerate the serologic and biochemical analysis of the cellular control of normal immunity in man.

Agammaglobulinemia↗
PubMed1978

Characterization of a suppressor-cell leukemia. Evidence for the requirement of an interaction of two T cells in the development of human suppressor effector cells.

To characterize the suppressor activity of neoplastic T cells from a child with acute lymphoblastic leukemia and hypogammaglobulinemia, we applied an in vitro assay that determines the capacity of pokeweed-mitogen-stimulated lymphocytes to mature into immunoglobulin-secreting cells. The geometric mean synthesis by peripheral blood lymphocytes from 12 normal persons was 3200 ng for IgM, 2447 ng for IgG and 1825 for IgA (2 X 10(6) cells per 12 days in culture). The patient's leukemic cells produced no detectable immunoglobulin and depressed the immunoglobulin production of normal lymphocytes by 85 to 100 per cent in co-culture experiments. However, suppression was observed only when co-operating normal T cells were present. Prior irradiation of either the leukemic T cells or the co-operating normal T cells nullified the suppressor effect. Therefore, an interaction between at least two different T-cell subsets may be required for the generation of suppressor effector T cells in man.

Agammaglobulinemia↗