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Biomedical subjects

R Parkman

Publications and source records attributed to R Parkman.

At least 19 recordsLinked to original sources
PubMed1999

Spontaneous apoptosis in lymphocytes from patients with Wiskott-Aldrich syndrome: correlation of accelerated cell death and attenuated bcl-2 expression.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and a progressive deterioration of immune function. WAS is caused by mutations in an intracellular protein, WASP, that is involved in signal transduction and regulation of actin cytoskeleton rearrangement. Because immune dysfunction in WAS may be due to an accelerated destruction of lymphocytes, we examined the susceptibility to apoptosis of resting primary lymphocytes isolated from WAS patients in the absence of exogenous apoptogenic stimulation. We found that unstimulated WAS lymphocytes underwent spontaneous apoptosis at a greater frequency than unstimulated normal lymphocytes. Coincident with increased apoptotic susceptibility, WAS lymphocytes had markedly attenuated Bcl-2 expression, whereas Bax expression did not differ. A negative correlation between the frequency of spontaneous apoptosis and the level of Bcl-2 expression was demonstrated. These data indicate that accelerated lymphocyte destruction by spontaneous induction of apoptosis may be one pathogenic mechanism by which the progressive immunodeficiency in WAS patients develops.

Adolescent↗
PubMed1999

Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count.

IL-7 is produced by stromal cells and is the major lympho- and thymopoietic cytokine. IL-7 induces proliferation and differentiation of immature thymocytes, and protects thymocytes from apoptosis by induction of bcl-2 expression. The regulation of IL-7 production is poorly characterized, although down-regulation by transforming growth factor-beta (TGF-beta) has been described. We measured the serum levels of IL-7 before and after bone marrow transplant (BMT) in 32 children undergoing BMT for genetic diseases (severe combined immune deficiency (SCID) and thalassemia), aplastic anemia, and acute lymphoblastic and non-lymphoblastic leukemia (ALL and ANLL). Prior to BMT, the highest IL-7 levels were observed in patients with SCID and ALL, i.e. those patients with genetic or acquired lymphopenia. Patients with thalassemia and ANLL had normal levels of IL-7. Over the 8 weeks following BMT, the IL-7 levels of patients with SCID and ALL fell as the absolute lymphocyte count (ALC) increased. No detectable change in IL-7 levels was observed in the patients with thalassemia and ANLL. Levels of IL-7 were highest in the young infants with SCID compared to the age-matched controls. Together, the data demonstrate that serum levels of IL-7 in lymphopenic patients are inversely related to patient age and the absolute lymphocyte count (ALC). The inverse relationship to ALC suggests that there is either direct regulation of stromal production or more likely, binding of secreted IL-7 to lymphocytes expressing IL-7 receptors.

Adolescent↗
PubMed1999

Defective anticarbohydrate antibody responses to naturally occurring bacteria following bone marrow transplantation.

The long-term recipients of allogeneic bone marrow transplantation (BMT) are at an increased risk of death due to bacterial infections. We evaluated the anticarbohydrate antibody responses of BMT recipients to a naturally occurring bacterial carbohydrate, polyribose phosphate (PRP). The recipients of autologous BMT achieved protective anti-PRP levels (>100 ng/mL) by 3 years after transplantation, with a pattern consistent with a recapitulation of the ontogeny of anticarbohydrate antibody responses. None of the six recipients of unrelated BMT who were off immunosuppressive therapy had protective anti-PRP levels, though their response to a protein antigen (tetanus toxoid) was normal. Of 48 recipients of histocompatible BMT, 22 (46%) had protective anti-PRP antibody levels, whereas 13 (27%) recipients who were >3 years post-BMT did not have protective levels. Therefore, all unrelated recipients and a significant proportion of histocompatible recipients without clinical graft-vs.-host disease had persistent and prolonged defects in their capacity to produce antibodies to naturally occurring bacterial carbohydrate antigens. These results suggest that allogeneic BMT recipients should be longitudinally evaluated for their anticarbohydrate antibody responses and that patients with defective antibody responses should receive prophylactic antibiotics or replacement immunoglobulin therapy or both to reduce their risk of late bacterial infections.

Adolescent↗
PubMed1998

Neonatal thymectomy: does it affect immune function?

OBJECTIVE: The purpose of this study was to determine whether thymectomy in the newborn has a negative effect on immune function. METHODS: Twenty-five neonates (<30 days) who had thymectomy at congenital heart repair were prospectively studied to determine immune function. The percentage of T-cell subtypes including CD3 (all T cells), CD4 (helper T cells), and CD8 (suppressor T cells) was determined. In six patients, further testing of CD4 cells was done to determine whether they were newly formed, recent thymic emigrants (CD4, CD45, and RA+), or older educated lymphocytes (CD4, CD45, and RO+). Response to the mitogen phytohemagglutinin and to tetanus toxoid were determined, as were antibody titers to tetanus. Samples were drawn before the thymectomy, at approximately 3 months after immunization and at 1 year. Ten age-matched control patients were tested. At follow-up, parents were asked about infections. RESULTS: Prethymectomy T-cell subsets were all normal and comparable to controls. At 12 months, the percent of CD3 was significantly less than in the control group (48% +/- 3% versus 64% +/- 2% [mean +/- standard error of the mean]; p < 0.01) as was CD4 (31% +/- 2% versus 46% +/- 2% [mean +/- standard error of the mean]; p = < 0.01). CD8 did not drop. Surprisingly, the percent of CD4 that were recent thymic emigrants did not decrease significantly (50% +/- 8% versus 60% +/- 6% [mean +/- standard error of the mean]; p = not significant). Lymphocyte blastogenesis to phytohemagglutinin and tetanus toxoid and antibody to tetanus were all normal at 12 months. No patient required readmission for infection, and there were the expected number of minor infectious events (median 3; 95% confidence interval 1,4). CONCLUSION: Thymectomy in neonates results in a modest but significant decrease in T-lymphocyte levels, but there is no compromise in immune function.

Antigens, CD↗
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

Chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) continues to be the major problem in the long-term survivors of allogeneic hematopoietic stem cell transplants. Because of its similarities to autoimmune disease, the pathogenesis of chronic GVHD has been thought to differ from acute GVHD. Autoreactive T lymphocytes are an important effector mechanism with interferon gamma playing a central role in the increased collagen deposition that is the central histopathologic feature of chronic GVHD. Therapies that prevent the development of acute GVHD have been unsuccessful in the prevention of chronic GVHD. None of the present therapies for established chronic GVHD are successful in the majority of patients.

Chronic Disease↗
PubMed1998

Hematopoietic stem cell transplantation for primary lymphoid immunodeficiencies.

Hematopoietic stem cell (HSC) transplantation is curative therapy for many primary immunodeficiencies. All forms of severe combined immune deficiency (SCID) can be cured, but the extent of the immunologic correction is dependent on the pathophysiology of the primary defect. Defects involving lymphocyte differentiation are more easily corrected than defects in lymphocyte function because a selective advantage exists for the progeny of the normal donor HSC when the primary defect affects lymphocyte differentiation. T-cell-depleted (TCD), haploidentical-HSC transplantation can cure many forms of SCID, but not other primary immunodeficiencies like the Wiskott-Aldrich syndrome (WAS). Unrelated bone marrow and umbilical cord blood are alternative sources of HSC for patients who do not have histocompatible donors.

Hematopoietic Stem Cell Transplantation↗
PubMed1997

Gene therapy for newborns.

Application of gene therapy to treat genetic and infectious diseases may have several advantages if performed in newborns. Because of the minimal adverse effect of the underlying disease on cells of the newborn, the relatively small size of infants, and the large amount of future growth, gene therapy may be more successful in newborns than in older children or adults. The presence of umbilical cord blood from newborns provides a unique and susceptible target for the genetic modification of hematopoietic stem cells. In our first trial of gene therapy in newborns, we inserted a normal adenosine deaminase gene into umbilical cord blood cells of three neonates with a congenital immune deficiency. The trial demonstrated the successful transduction and engraftment of stem cells, which continue to contribute to leukocyte production more than 3 years later. A similar approach may be taken to insert genes that inhibit replication of HIV-1 into umbilical cord blood cells of HIV-1-infected neonates. Many other metabolic and infectious disorders could be treated by gene therapy during the neonatal period if prenatal diagnoses are made and the appropriate technical and regulatory requirements have been met.

Adenosine Deaminase↗
PubMed1997

Immunological reconstitution following bone marrow transplantation.

The recipients of hematopoietic stem cell transplants are characterized by an immunodeficiency of varying severity and duration. Their immunoincompetence is due in part to: 1) a lack of sustained transfer of donor immunity, 2) a recapitulation of lymphoid ontogeny, 3) the effects of graft-versus-host disease and its therapy, and 4) a reduction in thymic function. Recipients can have delays in the production of naive T lymphocytes following transplantation which result in defects in the production of new antigen-specific T lymphocytes and an inability to produce antibodies, especially to carbohydrate antigens.

Animals↗
PubMed1995

Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow.

We have investigated the mechanism of tolerance in a patient with severe combined immunodeficiency (SCID) transplanted with HLA-haploidentical, T cell-depleted bone marrow cells obtained from the mother. At 4 years after transplantation, T cells, natural killer (NK) cells, and a small percentage (2%) of B cells were found to be of donor origin, whereas monocytes and the majority of B cells remained of host origin. In primary mixed lymphocyte cultures (MLC), the engrafted T cells of the donor did not proliferate in response to the host cells, whereas untransplanted donor T cells showed good proliferative responses. However, CD4+ and CD8+ T-cell clones of donor origin with specificity for class II and class I HLA determinants of the host were isolated. CD8+, host-reactive T-cell clones displayed normal cytotoxic activity after stimulation with the host cells, but proliferative responses of CD4+, host-reactive T-cell clones were considerably reduced. In addition, both CD8+ and CD4+, host-reactive T-cell clones produced very low to undetectable levels of interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3 zeta subunit of the T-cell receptor (TcR) was normal, and after stimulation via CD3, Raf-1 and p42 mitogen activated protein (MAP) kinase were phosphorylated, indicating that this part of the signaling pathway after triggering of the TcR/CD3 complex is present. These results, together with our previous observation that dysfunctional, host-reactive T-cell clones can be isolated in SCID patients transplanted with fetal liver stem cells, demonstrate that lack of clonal deletion of host-reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.

Bone Marrow Transplantation↗
PubMed1995

The effect of thymic function on immunocompetence following bone marrow transplantation.

We investigated the role of thymic function in the immunodeficiency that characterizes bone marrow transplantation (BMT) recipients. The capacity of histocompatible BMT recipients to generate new CD4+ T lymphocytes was determined by FACS analysis with antibodies to the two isoforms of CD45: CD45RA, which is expressed on newly generated CD4 T lymphocytes, and CD45RO, which is expressed on antigen-specific memory CD4 T lymphocytes. Immediately following BMT, all patients had low levels of CD45RA-expressing CD4 T lymphocytes, which increased during the first year and then stabilized. Since thymic function decreases with age in normal individuals, the impact of recipient age on the generation of new CD45RA,CD4 T lymphocytes was determined in BMT recipients with and without chronic graft-vs.-host disease (GVHD). In addition, antigen-specific immune function was determined by assessing in vitro blastogenic response to tetanus toxoid (TT). More than 1 year after transplantation, the results from BMT recipients without chronic GVHD were similar to those of normal individuals; there was an age-dependent decline in the number of CD45RA,CD4 T lymphocytes, and antigen-specific immune function was age-independent. On the other hand, recipients with chronic GVHD had an age-dependent decline in their immune function (r = 0.45 and p = 0.02) that correlated with the number of new CD45RA,CD4 T lymphocytes (p = 0.027) but not the number of memory CD45RO,CD4 T lymphocytes (p = 0.11). Thus recipients with chronic GVHD have decreased antigen-specific immune function that may be due to an acceleration of the normal thymic aging process induced by GVHD and its therapy.

Bone Marrow Transplantation↗