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PubMed1992

[Two cases of unclassified chronic myeloproliferative disorders].

Two cases of unclassified chronic myeloproliferative disorders (UCMPD), diagnosed by hematological, cytogenetic and DNA analyses, are described. Case 1: a 63 year old female was admitted because of leukocytosis (96,800/microliters) and splenomegaly. Hematological examinations revealed an increase of the granulocytes in the peripheral blood and bone marrow. The neutrophil alkaline phosphatase (NAP) score was 121. The patient developed blast crisis after 12 months of the chronic phase. Case 2: a 48 year old male was presented with fever and leukocytosis (20,000/microliters). Hematological examinations revealed an increase of granulocytes in the peripheral blood and bone marrow. The NAP score was 33. Maturation-arrest in granulocytic series and morphological abnormalities of marrow cells were not observed in the two cases. Cytogenetic analysis of bone marrow cells disclosed 46, XX, i (17 q) in case 1 and 47, XY, +8 in case 2. Southern blot analysis using 3' bcr probe and TransProbe-1 showed no bcr rearrangement. These cases are thought to be valuable in order to clarify the relationship between UCMPD and CMPD such as Ph1 negative chronic myelocytic leukemia and myelodysplastic syndromes.

Blast Crisis↗
PubMed1999

Abnormal patterns of immunoglobulin heavy chain gene DNA fingerprinting during chronic phase chronic myeloid leukemia.

Using IgH DNA fingerprinting we have previously demonstrated clonal immunoglobulin heavy chain (IgH) gene rearrangements during chronic phase (CP) chronic myeloid leukemia (CML) in patients destined to develop lymphoid blast crisis (L-BC). In view of this we decided to follow a cohort of CP CML patients to determine the frequency with which abnormal IgH fingerprints are found and their relationship, if any, to treatment regimen. Thirty three, initially CP, CML patients were studied on 111 occasions over a 16 month period using consensus PCR amplification of the third complementarity determining region (CDR3) of the IgH gene and high resolution polyacrylamide gel electrophoresis (IgH DNA fingerprinting). Of these 33 patients, thirteen received interferon-alpha (IFN) containing regimens and 15 non-IFN containing regimens throughout the study period. Five patients received variable therapy. During the period of observation 7 patients experienced disease progression: 5 accelerated phase, I L-BC and I myeloid blast crisis (M-BC). Abnormal IgH fingerprints were seen in 29 of the 111 (26%) specimens analysed. The 28 patients who received uniform therapy (IFN or non-IFN) over the 16 months were classified as "normal" (n = 18, normal pattern on all occasions) or "abnormal" (n = 10, abnormal on 1 or more occasions). Analysis by patient group (normal vs abnormal) showed that fingerprint abnormalities were associated with an elevated peripheral blood lymphocyte count (p = 0.0001) but not with changes in the total white cell count. Comparison of the IFN vs. non-IFN groups showed the former all had normal patterns whereas 10 of 15 non-IFN therapy patients were abnormal (p = 0.00023). The peripheral blood lymphocyte counts in the normal vs abnormal patients within the non-IFN group were not significantly different. The patient who developed L-BC demonstrated a persistent IgH fingerprint pattern abnormality from 7 months prior to the diagnosis of L-BC. The M-BC patient had a normal pattern at all times. We conclude that: (1) abnormal IgH fingerprints are found in a significant number of CP CML patients; (2) in this cohort the use of IFN was associated with normal CP CML IgH fingerprints, and (3) detection of abnormal IgH fingerprints may be highly predictive for the lineage of impending blast crisis.

DNA Fingerprinting↗
PubMed1985

Early T-cell features in blast crisis of Ph1-positive chronic myeloid leukaemia.

A patient with Ph1-positive chronic myeloid leukaemia (CML) presented in extramedullary blast crisis. Whereas the peripheral blood and bone marrow features were consistent with the chronic phase of CML, study of the enlarged lymph nodes demonstrated massive replacement by Ph1-positive blast cells of lymphoblastic morphology. Such blast cells showed diffuse acid phosphatase positivity, were positive for TdT, and had an enzyme pattern (adenosin-deaminase, purine-nucleosidephosphorilase and lactate-dehydrogenase) typical of immature T-cells. To further characterize the phenotype of the blast cells, they were analyzed for surface markers using a panel of monoclonal antibodies selected to identify differentiation antigens of T cells, B cells and myeloid cells. The results of the latter analysis were consistent with an early T-cell origin of the blast cells, since they were positive for TdT, CRIS1 (T1), E rosettes and OKT10, and were negative for OKT3, Leu3 and OKT8. These features demonstrate that T-cell markers may also be expressed in blast crisis of CML and provide evidence that T-cells may share a common stem cell with myeloid and B-cells in CML.

Adenosine Deaminase↗
PubMed1995

Effects of vitamin A on survival in patients with chronic myelogenous leukemia: a SWOG randomized trial.

A national cooperative group trial was conducted in 153 patients with chronic myelogenous leukemia (CML) in chronic phase treated with oral pulse busulfan to determine if oral vitamin A can increase the time to blast crisis and enhance survival of patients. Patients diagnosed within 1 year and in the chronic phase of CML were randomized to receive oral pulse busulfan or the alkylator plus continuous oral vitamin A. Distributions of clinical progression and overall survival were estimated using the method of Kaplan and Meier. Associations of these endpoints with treatment and other patient characteristics were analyzed using the proportional hazards regression method of Cox. Both regimes were well tolerated. Patients in the busulfan plus vitamin A arm had somewhat longer durations of clinical progression-free survival (median 46 months) and overall survival (51 months) compared to those in the busulfan arm (medians 38 and 44 months). However, the differences were not statistically significant (one-tailed P = 0.11 for clinical progression-free survival, 0.081 for survival). After adjustment for significant factors identified in an additional exploratory multivariate analysis, risk of clinical progression or death was 53% (P = 0.022) greater and risk of death 60% (P = 0.014) greater among busulfan patients. Given the relatively large though non-significant difference between treatment arms, the limited statistical power of the study, and the likelihood that oral vitamin A may not be the most effective means of delivering retinoid therapy, we conclude that further investigation of retinoids in chronic phase CML is warranted.

Antineoplastic Agents, Alkylating↗
PubMed1987

Loss of myeloid differentiation antigens precedes blastic transformation in chronic myelogenous leukemia.

In order to determine whether antigenic patterns alter with disease progression and are thereby suggestive of impending blast crisis in chronic myelogenous leukemia, 50 bone marrow biopsy specimens from 32 patients were examined retrospectively using indirect immunoperoxidase labeling with three monoclonal antibodies that detect myeloid antigens. Monoclonal antibodies PMN13F6, PMN7C3, and PMN8C7 detect human neutrophil antigens that first appear at the myeloblast, promyelocyte, and metamyelocyte stages of differentiation, respectively, and persist throughout later differentiation. Percentages of antigen-positive bone marrow cells during the chronic phase were compared with percentages of antigen-positive cells at blast transformation, and time from bone marrow biopsy until blast crisis was correlated with the percentage of bone marrow cells expressing these antigens. Bone marrow biopsy samples from patients in the chronic phase who continue to remain clinically stable 4 to 106 months after biopsy expressed PMN13F6 antigen on 82% +/- 9% (mean +/- SD) of cells, PMN7C3 antigen on 62% +/- 14% of cells, and PMN8C7 on 68% +/- 14% of cells. Bone marrow biopsy specimens obtained from patients 1 or more years prior to blast transformation expressed PMN13F6 antigen on 81% +/- 12%, PMN7C3 antigen on 71% +/- 16%, and PMN8C7 on 64% +/- 16% of cells. Bone marrow biopsy samples obtained between 2 months and 1 year prior to blast crisis expressed PMN13F6 antigen on 68% +/- 15%, PMN7C3 on 51% +/- 17%, and PMN8C7 antigen on 46% +/- 18% of cells. Bone marrow biopsy specimens taken at the time of blast transformation expressed PMN13F6 antigen on 20% +/- 25%, PMN7C3 antigen on 19% +/- 25%, and PMN8C7 antigen on 13% +/- 25% of cells. The difference between the mean of antigen-positive cells from bone marrow biopsy samples obtained at the time of blast crisis was significant compared with the mean of positive cells from biopsy specimens obtained at all other phases of the disease (P less than .001 for all three antibodies). There was a positive correlation between loss of myeloid antigens and disease progression as determined by simple regression of log time and correlation analysis (PMN13F6, r = .6533, P less than .005; PMN7C8, r = .6304, P less than .005; PMN8C7, r = .5215, P less than .05). There was a negative correlation between percentage of immature cells and time to blastic crisis (r = -.6206, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1995

DNA index and %S-phase cells determined in acute lymphoblastic leukemia of children: a report from studies ALL V, ALL VI, and ALL VII (1979-1991) of the Dutch Childhood Leukemia Study Group and The Netherlands Workgroup on Cancer Genetics and Cytogenetics.

DNA per cell content was routinely recorded by single-parameter flow cytometry in leukemic blasts from 473 children with acute lymphoblastic leukemia (ALL), enrolled in national studies ALL V, VI, and VII (1979-1991) of the Dutch Childhood Leukemia Study Group. The parameters bonemarrow %S-value and DNA Index were compared with clinical features, with chromosome number based on cytogenetic analyses and with treatment results in study ALL VI. %S-values, ranging between 1 and 36%, were unrelated to initial white blood cell count, immunophenotype, and DNA index but were lowest in blasts with L1 morphology. In study ALL VI (non-high risk), the survival of patients with < or = 6% S-phase cells was superior to that of patients with %S-values of > 6 (P = 0.030). Hyperdiploidy, defined by a DNA index > or = 1.16, was compared to the cytogenetic hyperdiploid classification of n > 50. Initially there were 25 discrepancies in 189 samples jointly analysed by flow cytometry and cytogenetics. After review only five discrepancies remained unresolved. Hyperdiploidy, independent of the method used, was found to be unrelated to blast morphology and %S-phase cells but closely associated with c-ALL and was absent in T-ALL. In study ALL VI, event-free survival at 8 years of hyperdiploid patients was 90.6% but was not significantly different from non-hyperdiploid patients (EFS = 82.1%; P = 0.08). Routine DNA flow cytometry appeared a valuable adjunct to cytogenetic analyses and allowed the identification of a large subset of non-high-risk ALL patients in study ALL VI with a DNA index > or = 1.16 or %S-value of < or = 6.0 with highest survival probability.

Bone Marrow↗
PubMed1986

Identical-twin (syngeneic) marrow transplantation for hematologic cancers.

The Seattle Marrow Transplant Team treated about 130 patients (age 4-68 yr) for hematologic cancer with supralethal chemoradiotherapy and bone marrow transplantation (BMT) from the normal genetically identical twin. The procedure was well tolerated. The principal problem was tumor resistance. Nevertheless, BMT for acute leukemia in relapse still cured about 20% of the patients. Moreover, BMT performed while in complete remission cured about 50% of patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. Sixteen patients received transplantation in the chronic phase of Ph1+ chronic granulocytic leukemia (CGL). All showed disappearance of all Ph1+ cells. Two died of pneumonitis. Of the 14 who are alive, 3 continue to have CGL 37-76 months after BMT and 11 remain in complete hematologic and cytogenetic remission without any Ph1+ metaphases at 31-108 months (median = 68) after BMT. Thus the Ph1-positive clone can be ablated and blast crisis prevented. BMT in the accelerated or blastic phase was far less effective. Syngeneic BMT also benefited or cured patients with lymphoma, hairy-cell leukemia, and multiple myeloma. Therefore, BMT should be considered for every patient who has a hematologic cancer and an identical twin.

Acute Disease↗
PubMed1992

[Treatment of blast crisis of chronic myeloid leukemia].

Up-date of chemotherapy in the accelerated and blastic phases of CGL has been done. Cytostatic therapy, even very intensive, remains ineffective in the eradication of pathological cellular clones as well as interferons therapy. The unique chance of being cured for a small cohort of patients with accelerated or blastic disease is allogeneic bone marrow transplantation. An effective treatment of these phases of CGL remains to be solved in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1981

Cellular proliferation in the spleen of DBA/2 mice infected with a myeloproliferative sarcoma virus(MPSV).

Cellular proliferation kinetics were investigated in the spleens of DBA/2 mice infected with a myeloproliferative sarcoma virus (MPSV) at three distinct phases of spleen growth: the rapid-growth phase, the slow-growth phase and the regression phase. Using injection of tritiated thymidine in vivo and autoradiographic techniques, we showed that most blast cells proliferate rapidly (cell cycle is equal to 10 h) even during the slow-growth phase. Very massive and rapid cell loss was found during the rapid-growth phase (cell loss factor phi = 80%). By comparing the decrease in specific splenic activity after in vivo injection of 125IUdR and 3HTdR, we were able to show a large reutilization of tritiated thymidine (R = 57%), visible less than 7 h after injection of isotopic DNA precursors. Thus, MPSV-infected spleen cells were shown, for the most part, to be short-lived cells: almost one-half mature into erythrocytes and the others rapidly die in situ.

Animals↗
PubMed1988

Studies of purine and tiazofurin metabolism in drug sensitive human chronic myelogenous leukemia K 562 cells.

Antineoplastic activity of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is mediated by an anabolite of the drug thiazole-4-carboxamide adenine dinucleotide (TAD), an analog of NAD which inhibits IMP dehydrogenase activity resulting in the depletion of guanylate pools and cell death. Human chronic myelogenous leukemia K 562 cells were found to be sensitive to tiazofurin with an IC50 of 19.2 microM. TAD content in K 562 cells (1.3 nmol/10(9)/h) was in the range found in susceptible murine and human tumor cells. Studies were conducted to relate tiazofurin toxicity with biochemical effects by examining nucleotide pools. Among the nucleotides, only guanylate pools were significantly depleted by the drug. To further study the effect of the drug on the purine nucleotide de novo and salvage biosynthetic pathways, flux of radiolabelled formate and guanine was employed. The results showed that de novo synthesis of guanylates was curtailed primarily by the drug's action without influencing adenylate biosynthesis or salvage of guanine to guanylates. These studies show that K 562 cells are sensitive to selective inhibition of de novo guanylate pathway indicating that human chronic myelogenous leukemia in blast crisis might be a good candidate for Phase II clinical trials with tiazofurin.

Carbon Radioisotopes↗
PubMed1989

Differences in bone marrow cytogenetic characteristics between treated and untreated myeloma.

Clonal karyotypic abnormalities in myelomatosis at initial diagnosis have been widely studied, but little data are available on the karyotypic status following treatment. We have studied bone marrow (BM) from 17 cases of untreated myelomatosis at initial diagnosis and from a further 29 cases who had received chemotherapy with regimens containing alkylating agents. At the time of study all previously treated cases had been off treatment for at least 152 days, had a paraprotein level in plateau phase, had a BM with less than 4% blasts, and in 28 of these 29 cases had less than 20% BM plasma cells. Two cases had more than 15% BM ringed sideroblasts; one other case was transfusion dependent. Clear differences in cytogenetic characteristics between the two groups were seen. At initial diagnosis clonal karyotypic abnormalities were observed in six of 11 accessible cases. All had hyperdiploid clones (of 49-54 chromosomes) and showed characteristic involvement of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. Additional structural rearrangements were present in only two of these cases. Following treatment, clonal abnormalities were seen in 10 of 25 assessible cases, of which only two showed hyperdiploidy (one with a hyperdiploid line, one with an additional derived chromosome). The remaining eight showed hypodiploid or pseudodiploid lines, and seven of these showed complex karyotypes with multiple rearrangements particularly affecting chromosomes 1, 2, 3, 6 and 7. After a minimum follow-up of 16 months, only four of these 10 cases (40%) remain alive compared with 12 of 15 (80%) with a normal karyotype after treatment (P = 0.03). No correlation was observed between the presence of an abnormal karyotype and the total dose or timing of previous therapy, though cases with an abnormal karyotype tended to have received treatment for longer (790 +/- 166 days) than cases with a normal karyotype (486 +/- 50 days). It is not clear whether the ploidy difference between the two groups represents a change in the disease state due to treatment or a direct effect of treatment itself.

Aged↗
PubMed2004

Antisense inhibition of Bcr-Abl/c-Abl synthesis promotes telomerase activity and upregulates tankyrase in human leukemia cells.

Clinical studies in chronic myelogenous leukemia demonstrate that the overexpression of Bcr-Abl tyrosine kinase is usually accompanied by relatively low telomerase activity in the chronic phase, which reverts to a high activity in blast crisis. The present study was designed to investigate the cross-talk between both enzymes, using Bcr-Abl-positive K-562 and Bcr-Abl-negative Jurkat cell lines, treated with antisense oligodeoxyribonucleotides (ODNs) against Bcr-Abl/c-Abl mRNA. The decreased amount and enzyme activity of Bcr-Abl/c-Abl provoked telomerase activation in both cell lines. After short-term treatment with anti-Bcr-Abl/c-Abl ODNs (6 days), no variations in hTERT and phospho-hTERT were detected. The decreased amount of Bcr-Abl/c-Abl was accompanied by: alterations in telomeric associated proteins-overexpression of tankyrase and decreased amount of TRF1/Tin2, cell growth arrest of K-562 cells, reaching a plateau after 6 days treatment, and increased proliferating activity of Jurkat cells. No changes in telomere length were detected after short-term treatment. In contrast, after long-term treatment with anti-Bcr-Abl/c-Abl ODNs (36 days), a significant elongation of telomeres and enhancement of hTERT were established, accompanied by an increased proliferating activity of both cell lines. These data provide evidence that the inhibition of Bcr-Abl or c-Abl synthesis keeps a potential to restore or induce cell proliferation through telomere lengthening control and telomerase activation.

Base Sequence↗
PubMed2004

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.

Animals↗
PubMed1997

A pilot study of all-trans retinoic acid in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

Retinoids have significant antiproliferative effect against chronic myelogenous leukemia (CML) cells in vitro. We conducted a pilot study to investigate the clinical effect of all-trans retinoic acid (ATRA) in patients with CML. Thirteen patients with Philadelphia chromosome (Ph)-positive CML in late chronic phase (n=7), accelerated phase (n=5), or blastic phase (n=1) were treated. All had been previously treated and 12 (92%) had disease refractory to interferon-alpha therapy. They received ATRA 175 mg/m2 orally in two divided doses daily until disease progression. The median duration of therapy was 56 days (range 11 to 190). Only one patient in late chronic phase had a transient decrease in WBC counts; all other patients in late chronic phase showed no response to therapy. Four of the five patients in accelerated phase showed evidence of antileukemia effect manifested by a decrease in bone marrow and/or peripheral blood blasts, promyelocyte and/or basophil percentages. In all cases the response was transient. The patient in blastic phase had no evidence of antileukemic effect. The treatment was well tolerated with the major side-effects being headache, nausea, dry skin, and dry mucosal membranes. One patient required dose reductions due to toxicity. We conclude that in this population of patients with extensively treated, advanced stage, Ph-positive CML, ATRA alone is ineffective for long-term therapy. The antileukemia effect seen in some patients warrants further investigation of retinoids in other schedules and in combinations in patients with CML.

Adolescent↗
PubMed2006

Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha.

Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.

Animals↗
PubMed1998

Activation-dependent expression of the insulin-like growth factor binding protein-2 in human lymphocytes.

The expression of the insulin-like growth factor binding protein-2 (IGFBP-2) was assayed in mononuclear cells originating from different organs of the immune system. All mononuclear cells studied did express IGFBP-2, but the expression level was found to be dependent on the cell type and origin of the cell. T cells showed a higher expression of IGFBP-2 mRNA than did B cells, and CD34+ stem cells expressed IGFBP-2 mRNA at a high level. Expression was highest in bone marrow and thymus. Stimulation of peripheral mononuclear cells resulted in a marked increase of IGFBP-2 mRNA and also intracellular IGFBP-2, as analysed by fluorescence staining. This increase parallels the increase of other known T-cell activation markers. Furthermore, the increase of intracellular IGFBP-2 seems to precede T-cell blast formation and all T cells in active phases of the cell cycle have high levels of IGFBP-2. Our results provide a basis for further investigations on the contribution of the IGF-system to the regulation of T-cell proliferation and differentiation. IGFBP-2, in particular, may have an important influence in the regulation of T-cell activation and proliferation.

Cell Culture Techniques↗
PubMed1993

Differential regulation of surface immunoglobulin and Lyb2 mediated B cell activation: II. cAMP dependent (prostaglandin E2) and independent (IFN-gamma) mechanisms of regulation of B lymphocyte activation.

We have recently demonstrated that pharmacological agents that elevated cAMP inhibited slgM but not Lyb2 mediated activation of murine B lymphocytes. In this report we show evidence for differential regulation of prostaglandin E2 (PGE2), a physiological agent that elevated cAMP and IFN-gamma on slgM and Lyb2 mediated B cell activation. PGE2 inhibited anti-IgM but not anti-Lyb2 induced DNA synthesis in a dose-dependent manner. Interestingly, rIFN-gamma also inhibited anti-Ig but not anti-Lyb2 induced DNA synthesis. rIFN-gamma exerted its effects directly on B cells since depletion of T cells and G-10 Sephadex adherent cells did not alter effects of IFN-gamma on anti-IgM and anti-Lyb2 induced DNA synthesis. Pretreatment of B cells with IL-4 and/or IL-5 did not prevent the IFN-gamma mediated inhibition of the anti-IgM response. The inhibitory effect of IFN-gamma was observed during early stages of B cell activation. Thus IFN-gamma inhibited anti-mu induced blast transformation and subsequent progression into the G1 phase of the cell cycle. The differential effects exerted by PGE2 and rIFN-gamma appeared to be mediated by distinct mechanisms. Thus PGE2 but not rIFN-gamma, at concentrations inhibitory to the slgM response, induced elevation of intracellular cAMP levels. These results demonstrate that physiologically relevant immunomodulators such as PGE2 and IFN-gamma can differentially regulate murine B cell responses mediated through the antigen receptor and Lyb2 molecules by cAMP dependent and independent mechanisms. Relevance of this regulation for the induction of antibody synthesis by Th1 and Th2 types of helper T cells is discussed.

Animals↗