Apoptosis parallels lymphopoiesis in bone marrow transplantation and HIV disease

Donnenberg, Albert D.; Margolick, Joseph B.; Beltz, Lisa A.; Donnenberg, Vera S.; Rinaldo, Charles R.

doi:10.1016/0923-2494(96)80236-7

Cited by 27 publications

(9 citation statements)

References 17 publications

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“…Indeed, an increased rate of T cell SA after BMT has already been described, decreasing with time. 3 We confirmed the increased rate of SA, and demonstrated also an increased susceptibility to AICD after re-stimulation in vitro with mitogens. Moreover, as expected according to our hypothesis, the progressive recovery of T cell proliferative response in vitro was correlated with the decrease of both SA and AICD.…”

Section: Discussionsupporting

confidence: 70%

“…Interestingly, it has been demonstrated that peripheral blood T cells regenerating after BMT are highly susceptible to in vitro spontaneous apoptosis (SA). 3 This process results from inadequate stimulation and can be prevented by growth factors such as IL-2 and by activation of genes such as bcl-2. [4][5][6] A different process of lymphocyte cell death results from repeated activation.…”

mentioning

confidence: 99%

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Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death

Brugnoni

Airò

Pennacchio

et al. 1999

Bone Marrow Transplant

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Summary:We have studied the regeneration of T cell subsets and function after BMT in 21 children affected by combined immunodeficiency after BMT. In the first months, the striking predominance of CD4 ؉ cells displayed the primed CD45R0؉ phenotype and a high number of activated (HLA-DR ؉ ) T cells were observed. Regeneration of naive CD4 + CD45RA + cells correlated with the recovery of proliferative responses to mitogens (r ‫؍‬ 0.64, P Ͻ 0.001). Peripheral blood lymphocytes circulating after BMT undergo an increased process of in vitro cell death, resulting from two mechanisms: spontaneous apoptosis (SA), a consequence of defective production of IL-2 and down-regulation of Bcl-2 (P = 0.02 vs healthy controls), and high susceptibility to activation-induced cell death (AICD) after restimulation with mitogens. In accordance with the role of CD95/Fas in this latter process, we have observed a high level of CD95 expression (P Ͻ 0.001 vs healthy controls), correlated with AICD (P Ͻ 0.001) but not with SA, and decreasing with time after BMT (P Ͻ 0.001). Both SA and AICD levels correlated with the presence of activated T cells and decreased with the progressive recovery of T cell proliferative response. Therefore, the lymphocyte hyperactivated status might explain their susceptibility to apoptosis and contribute to the genesis of immunodeficiency that follows BMT. Keywords: bone marrow transplant; severe combined immunodeficiency; Fas; Bcl-2; apoptosis The majority of primary immunodeficiency disorders results from abnormalities in the differentiation or function of immunocompetent cells originating from haemopoietic stem cells. Stem cell transplantation, generally performed with BMT, therefore offers a therapeutic approach in these patients.1,2 Recovery of the T cell number after BMT is slow. The recovery of T cell function is even slower, causCorrespondence: Dr P Airò,

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Section: Discussionsupporting

confidence: 70%

mentioning

confidence: 99%

Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death

Brugnoni

Airò

Pennacchio

et al. 1999

Bone Marrow Transplant

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“…The percentage of NK cells in the pre-GdG, peak, which were presumably undergoing apoptosis, was 54.5 YO in cultures with 3G8 mAb + IL-2; 28.3 % in 3G8 and 25.4 % in IL-2. Fluorescence of PI was lower in apoptotic cells, reflecting DNA fragmentation [20]. As a control for apoptosis, NK cells were subjected to mild hyperthermia prior to analysis: 40% of these cells were detected in the pre-GdG, peak (data not shown).…”

Section: Mechanism Of Decreased Nk Proliferation In the Presence Of 3mentioning

confidence: 99%

“…The data acquisition for analyses of the cell cycle or apoptosis was performed as described [19]. Samples of medium-treated NK cells exposed to 0.2% NaN3 were used as a positive control for necrosis, and NK cells incubated in medium alone for 24 h, exposed to 42 "C (mild hyperthemia) for 30 min and then incubated at 37 "C for additional 24 h, were used as a positive control for apoptosis [20].…”

Section: Flow Cytometric Analysis Of Apoptosis and The Cell Cyclementioning

confidence: 99%

Divergent effects of FcγRIIIA ligands on the functional activities of human natural killer cells in vitro

Sulica¹,

Metes²,

Gherman³

et al. 1996

Eur J Immunol

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The Fc gamma receptor (R)IIIA (CD 16) plays an important role in regulating the cytotoxic and non-cytotoxic functions of human natural killer (NK) cells. Some anti-CD 16 monoclonal antibodies (mAb) have been shown to stimulate NK activity, while human monomeric (m) IgG induces dose-dependent inhibition of NK activity. To explore further these interactions mediated via Fc gamma RIIIA, purified NK cells were cultured for 2-3 days in the presence of mIgG, 3G8 mAb, interleukin-2 (IL-2) or a combination of mIgG or 3G8 with IL-2. Binding of mIgG or 3G8 to Fc gamma RIIIA induced divergent effects of functions of cultured NK cells: 3G8 mAb + IL-2 induced dose-dependent inhibition of proliferation attributable to apoptosis; in contrast, mIgG + IL-2 significantly increased NK cell proliferation. Incubation of NK cells in the presence of mIgG up-regulated expression of surface activation markers (CD69, IL-2R alpha, ICAM-1), cytotoxicity, cytokine production (IL-1 beta, IFN-gamma and TNF-alpha) and release of soluble IL-2R. Thus, mIgG binding to Fc gamma RIIIA induced stimulatory signals in human NK cells, leading to up-regulation of IL-2R alpha expression, cell proliferation and cytokine release.

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“…In contrast, under inflammatory conditions, factors (e.g., proinflammatory cytokines, secondary effector populations, direct tissue injury by TBI) other than the susceptibility of donor T cells to undergo passive apoptotic cell death appear to have a more dominant role in determining the severity of GVHD than variables that modulate T cell survival. Given the emerging role of apoptosis in the pathophysiology of GVHD and allogeneic marrow transplantation (7,8,46), further studies to investigate the specific mechanisms that regulate apoptosis in BMT recipients are warranted. …”

Section: Discussionmentioning

confidence: 99%

Role of the Passive Apoptotic Pathway in Graft-Versus-Host Disease

Drobyski

Komorowski²,

Logan

et al. 2002

The Journal of Immunology

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Donor T cells have been shown to undergo apoptosis during graft-vs-host disease (GVHD). Although active apoptosis mediated through Fas/Fas ligand interactions has been implicated in GVHD, little is known about the role of the passive apoptotic pathway. To examine this question, we compared the ability of normal donor T cells and T cells overexpressing the antiapoptotic protein, Bcl-xL, to mediate alloreactive responses in vitro and lethal GVHD in vivo. In standard MLCs, T cells that overexpressed Bcl-xL had significantly higher proliferative responses but no difference in cytokine phenotype. Overexpression of Bcl-xL prolonged survival of both resting and alloactivated CD4+ and CD8+ T cells as assessed by quantitative flow cytometry, accounting for the higher proliferative responses. Analysis of engraftment in murine transplantation experiments demonstrated an increase in donor T cell chimerism in animals transplanted with Bcl-xL T cells, suggesting that overexpression of Bcl-xL prolonged T cell survival in vivo as well. Notably, transplantation of Bcl-xL T cells into nonirradiated F1 recipients also significantly exacerbated GVHD as assessed by mortality and pathological damage in the gastrointestinal tract. However, when mice were irradiated no difference in GVHD mortality was observed between animals transplanted with wild-type and Bcl-xL T cells. These data demonstrate that the passive apoptotic pathway plays a role in the homeostatic survival of transplanted donor T cells. Moreover, the susceptibility of donor T cells to undergo passive apoptosis is a significant factor in determining GVHD severity under noninflammatory but not inflammatory conditions.

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Apoptosis parallels lymphopoiesis in bone marrow transplantation and HIV disease

Cited by 27 publications

References 17 publications

Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death

Immune reconstitution after bone marrow transplantation for combined immunodeficiencies: down-modulation of Bcl-2 and high expression of CD95/Fas account for increased susceptibility to spontaneous and activation-induced lymphocyte cell death

Divergent effects of FcγRIIIA ligands on the functional activities of human natural killer cells in vitro

Role of the Passive Apoptotic Pathway in Graft-Versus-Host Disease

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