Showing papers by "Jennifer M. Puck published in 2002"
TL;DR: Caspase-8 deficiency in humans is compatible with normal development and shows that caspases has a postnatal role in immune activation of naive lymphocytes, which leads to immunodeficiency.
Abstract: Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.
676 citations
TL;DR: An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions.
318 citations
TL;DR: It is shown that with the use of a drug-selectable marker gene, chemotherapy can select for cells that express an otherwise nonselected therapeutic gene in blood and bone marrow.
Abstract: Unstable expression of transferred genes is a major obstacle to successful gene therapy of hematopoietic diseases. We have investigated in a canine large-animal model whether expression of transduced genes can be recovered in vivo. Mixed-breed dogs had undergone autologous bone marrow transplantation (BMT) with stem cell factor and granulocyte–colony-stimulating factor-mobilized retrovirally marked hematopoietic cells. The bicistronic retroviral vector construct allowed for coexpression of MDR1 and human IL-2 receptor common γ-chain cDNAs. The latter gene is deficient in X-linked severe combined immunodeficiency. After initial high-level expression, P-glycoprotein and the γ-chain were undetectable in blood and bone marrow 17 months post-BMT. Six months later, one dog was treated i.v. with 125 mg/m2 paclitaxel. Three administrations restored expression of the two linked genes to high levels in blood and bone marrow. Two dogs treated with higher paclitaxel doses died from myelosuppression after the first administration. As determined by flow cytometry, both genes were expressed in granulocytes, monocytes, and lymphocytes of the surviving animal. PCR analysis of DNA from peripheral blood confirmed that the retroviral cDNA was increased after paclitaxel treatment, suggesting enrichment of transduced cells. P-glycoprotein was detectable for more than 1 year after cessation of paclitaxel. Repeated analyses of blood and bone marrow aspirates gave no indication of hematopoietic disturbance after BMT with transduced cells and paclitaxel treatment. In summary, we have shown that with the use of a drug-selectable marker gene, chemotherapy can select for cells that express an otherwise nonselected therapeutic gene in blood and bone marrow.
32 citations
TL;DR: It is found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers or producing interferon-gamma and IL-2, and DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines.
17 citations
TL;DR: It is suggested that gene transfer to autologous peripheral CD34(+) cells using MFGS-gc retrovirus may benefit XSCID patients with persistent T- and B-cell deficits despite prior BMT.
14 citations
TL;DR: In this paper, the authors studied biochemical characteristics of T cells upon activation and found that defective MRL T cell activation, in part due to hypo-active IL-2, underlies the impaired apoptosis of this strain.
Abstract: Apoptosis of activated lymphocytes is crucial to the maintenance of immune homeostasis and self-tolerance, as demonstrated by the well-known autoimmune MRL lpr mouse lacking the death receptor Fas. However, even MRL+/+ activated T cells have a resistance to Fas-mediated apoptosis as compared to T cells from the non-autoimmune FVB/N strain. To understand the molecular mechanisms underlying these strain differences, we studied biochemical characteristics of T cells upon activation. Compared to FVB/N T cells, MRL T cells under-expressed procaspase-3 but over-expressed FLIP(L). In addition, up-regulation of Bcl-x(L), IL-2, and CD25 was diminished in MRL cells, suggesting inadequate T cell activation. Upon finding that MRL, like other autoimmune strains NOD and SJL, has a hypo-active variant of the IL-2 gene, we added wild-type murine recombinant (mr)IL-2 during activation. Exogenous mrIL-2 restored MRL apoptosis to the level of FVB/N; in addition, expression of procaspase-3, and FLIP(L), Bcl-x(L) and CD25 was normalized. These results suggest that defective MRL T cell activation, in part due to hypo-active IL-2, underlies the impaired apoptosis of this strain. In addition, the hypo-active variant of IL-2 shared among autoimmune strains may, by causing diminished cell activation and cell death, predispose these strains to develop autoimmune disease.
13 citations