scholarly journals Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2335-2342 ◽  
Author(s):  
DJ Gottlieb ◽  
HG Prentice ◽  
HE Heslop ◽  
C Bello-Fernandez ◽  
AC Bianchi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Killer Cell ◽  
Interleukin 2 ◽  
High Dose ◽  
Allogeneic Bone ◽  
Major Histocompatibility ◽  
Cell Numbers ◽  
Lak Activity

Abstract Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.

scholarly journals Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2335-2342 ◽  
Author(s):  
DJ Gottlieb ◽  
HG Prentice ◽  
HE Heslop ◽  
C Bello-Fernandez ◽  
AC Bianchi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Killer Cell ◽  
Interleukin 2 ◽  
High Dose ◽  
Allogeneic Bone ◽  
Major Histocompatibility ◽  
Cell Numbers ◽  
Lak Activity

Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.

scholarly journals Interleukin 2-activated killer cells in patients following transplants of soybean lectin-separated and E rosette-depleted bone marrow

Blood ◽  
1987 ◽  
Vol 70 (6) ◽  
pp. 1893-1903 ◽  
Author(s):  
CA Keever ◽  
K Welte ◽  
T Small ◽  
J Levick ◽  
M Sullivan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells ◽  
Lak Activity

Abstract During the early period following bone marrow transplantation before the immune system has reached full functional maturity, unprimed, nonspecific lytic systems may play a critical role as antiviral or antitumor effectors. The reconstitution of cells with this potential is of particular importance in recipients of bone marrow that has been depleted of mature T lymphocytes to prevent graft v host disease (GVHD). We examined the recovery of natural killer (NK) cells and interleukin 2 (IL 2)-augmented lymphokine-activated killer cells (LAK) in 48 patients at various intervals following transplantation of bone marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep RBCs (SBA-E- BMT). We found normal levels of both NK and LAK activity as early as 3 weeks following SBA-E- BMT. When compared with cells from controls, NK and LAK precursors from transplant recipients appeared to be activated in vivo in that freshly isolated peripheral blood mononuclear cells (PBMCs) from patients had an elevated cytolytic activity toward NK-insensitive targets and a more rapid response to activation by IL 2. In patients as well as controls, both LAK precursors and LAK effectors lacked antigens present on mature T lymphocytes (CD3, CD4, or CD8) but expressed antigens present on NK cells (CD2, CD16, and NKH1A). The LAK cells did not lyse either donor or host peripheral blood T cell targets. The activity of NK effectors but not LAK precursors survived the in vivo total body irradiation used for pretransplant conditioning in three patients studied. LAK precursors could be demonstrated as early as 18 days following transplant at a time when the bone marrow contained primarily donor- derived cells. Little or no LAK activity could be generated from cells of the SBA-E- BM graft itself, suggesting that LAK precursors differentiate rapidly from more primitive progenitors in the marrow graft. Thus, our data indicate that the NK and LAK lytic systems are among the earliest activities to recover during immune reconstitution following T cell-depleted BMTs.

scholarly journals Interleukin 2-activated killer cells in patients following transplants of soybean lectin-separated and E rosette-depleted bone marrow

Blood ◽  
1987 ◽  
Vol 70 (6) ◽  
pp. 1893-1903 ◽  
Author(s):  
CA Keever ◽  
K Welte ◽  
T Small ◽  
J Levick ◽  
M Sullivan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells ◽  
Lak Activity

During the early period following bone marrow transplantation before the immune system has reached full functional maturity, unprimed, nonspecific lytic systems may play a critical role as antiviral or antitumor effectors. The reconstitution of cells with this potential is of particular importance in recipients of bone marrow that has been depleted of mature T lymphocytes to prevent graft v host disease (GVHD). We examined the recovery of natural killer (NK) cells and interleukin 2 (IL 2)-augmented lymphokine-activated killer cells (LAK) in 48 patients at various intervals following transplantation of bone marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep RBCs (SBA-E- BMT). We found normal levels of both NK and LAK activity as early as 3 weeks following SBA-E- BMT. When compared with cells from controls, NK and LAK precursors from transplant recipients appeared to be activated in vivo in that freshly isolated peripheral blood mononuclear cells (PBMCs) from patients had an elevated cytolytic activity toward NK-insensitive targets and a more rapid response to activation by IL 2. In patients as well as controls, both LAK precursors and LAK effectors lacked antigens present on mature T lymphocytes (CD3, CD4, or CD8) but expressed antigens present on NK cells (CD2, CD16, and NKH1A). The LAK cells did not lyse either donor or host peripheral blood T cell targets. The activity of NK effectors but not LAK precursors survived the in vivo total body irradiation used for pretransplant conditioning in three patients studied. LAK precursors could be demonstrated as early as 18 days following transplant at a time when the bone marrow contained primarily donor- derived cells. Little or no LAK activity could be generated from cells of the SBA-E- BM graft itself, suggesting that LAK precursors differentiate rapidly from more primitive progenitors in the marrow graft. Thus, our data indicate that the NK and LAK lytic systems are among the earliest activities to recover during immune reconstitution following T cell-depleted BMTs.

scholarly journals Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells.

1983 ◽  
Vol 158 (4) ◽  
pp. 1356-1361 ◽  
Author(s):  
E A Grimm ◽  
R J Robb ◽  
J A Roth ◽  
L M Neckers ◽  
L B Lachman ◽  
...  
Keyword(s):  
Protein Purification ◽  
Peripheral Blood ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Peripheral Blood Lymphocytes ◽  
Lymphokine Activated Killer Cells ◽  
Blood Lymphocytes ◽  
Direct Activation ◽  
Activation Factor ◽  
Dependent Cell

Purified interleukin 2 (IL-2) was found to be sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer (LAK) cells. The LAK activation factor was directly and consistently associated with IL-2 activity using classic protein purification techniques, adsorption to IL-2-dependent cell lines, and inhibition with anti-Tac antibody. As yet, no other cytokines have been found that perform the same role.

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

scholarly journals IL-2 coordinates IL-2–producing and regulatory T cell interplay

2013 ◽  
Vol 210 (12) ◽  
pp. 2707-2720 ◽  
Author(s):  
Inês F. Amado ◽  
Julien Berges ◽  
Rita J. Luther ◽  
Marie-Pierre Mailhé ◽  
Sylvie Garcia ◽  
...  
Keyword(s):  
T Cell ◽  
Quorum Sensing ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Cell Numbers ◽  
Regulatory Circuit ◽  
Reporter Mice ◽  
Lymphocyte Homeostasis

Many species of bacteria use quorum sensing to sense the amount of secreted metabolites and to adapt their growth according to their population density. We asked whether similar mechanisms would operate in lymphocyte homeostasis. We investigated the regulation of the size of interleukin-2 (IL-2)–producing CD4+ T cell (IL-2p) pool using different IL-2 reporter mice. We found that in the absence of either IL-2 or regulatory CD4+ T (T reg) cells, the number of IL-2p cells increases. Administration of IL-2 decreases the number of cells of the IL-2p cell subset and, pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while increasing T reg cell numbers. We propose that control of the IL-2p cell numbers occurs via a quorum sensing–like feedback loop where the produced IL-2 is sensed by both the activated CD4+ T cell pool and by T reg cells, which reciprocally regulate cells of the IL-2p cell subset. In conclusion, IL-2 acts as a self-regulatory circuit integrating the homeostasis of activated and T reg cells as CD4+ T cells restrain their growth by monitoring IL-2 levels, thereby preventing uncontrolled responses and autoimmunity.

scholarly journals In vivo production of interleukin-5, granulocyte-macrophage colony- stimulating factor, macrophages colony-stimulating factor, and interleukin-6 during intravenous administration of high-dose interleukin-2 in cancer patients [see comments]

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 1981-1987 ◽  
Author(s):  
MR Schaafsma ◽  
JH Falkenburg ◽  
JE Landegent ◽  
N Duinkerken ◽  
S Osanto ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Interleukin 2 ◽  
Mononuclear Phagocytes ◽  
High Dose ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Stimulating Factor

Abstract Recombinant human interleukin-2 (IL-2), administered to cancer patients by continuous intravenous (IV) infusion (3 x 10(6) U/m2/d), was found to induce the in vivo production of colony-stimulating factors (CSF). Plasma obtained from patients during IL-2 treatment stimulated in vitro colony formation of normal human bone marrow cells, depleted of mononuclear phagocytes and T lymphocytes. This colony-stimulating activity (CSA) was identified as IL-5, granulocyte-macrophage CSF (GM- CSF), and macrophage CSF (M-CSF), by the ability of specific antibodies against these factors to neutralize their effects. The presence of IL-2- induced GM-CSF and M-CSF was also demonstrated by specific radioimmunoassays. During IL-2 treatment, plasma also contained detectable levels of IL-6, which was measured in a bioassay. Using a cDNA-polymerase chain reaction (PCR) with specific primer sets for the various CSF, we showed that IL-2 treatment induced the expression of mRNA for M-CSF, GM-CSF, IL-3, and IL-5, but not for granulocyte CSF (G- CSF) in peripheral blood mononuclear cells, suggesting differential expression of CSF in vivo in response to IL-2. Furthermore, no negative regulators of hematopoiesis, such as interferon gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF-alpha), were found in plasma. These data illustrate that in vivo administration of high-dose IL-2 may result in a stimulatory effect on hematopoiesis. The induction of detectable levels of IL-5 and GM-CSF in the circulation may explain the eosinophilia and neutrophilia observed in these patients.

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