[Case report: Acro-necrosis of the upper limbs caused by gemcitabine therapy]. / Acronecrosi degli arti superiori da gemcitabina: segnalazione di un caso clinico.

INTRODUCTION: Even if infrequent, a digital necrosis after chemotherapy can occur in cancer patients. The gemcitabine is generally well tolerate; the cutaneous toxic ulcerations only in 0.3% of the cases induces the suspension of the treatment. CLINICAL CASE: A 70 year old patient, female, with a bladder cancer, after a trans-urethral resection, is submitted to adjuvant chemotherapy with Gemcitabine 1700 mg (total dose/die), with administration in the days 1st and 8th, while in the 15th day was not effected because, to distance of 3-4 days from the second administration, appear paresthesies of the fingers of the hands, together with Raynaud type phenomenon, 38-39 degrees C intermittent fever, digital necrosis and fingertips gangrene. Laboratory: (Normal): RF; AutoAb: AMA, ASMA, APCA, anti-DNA; ENA; lupus anti-coagulant; Ab-anti-cardiolipin; C3-C4, CIC; homocysteine, anti-thrombin, protein C, protein S, mutation of the factor V of Leiden, plasminogen, alfa 2-antiplasmin. (Altered): Auto-antibody: ANA (on Hep-2): positive (title 1/160, speckled pattern), cryoglobulin positive, ESR 29; Instrumental examinations: Superior Limbs Angiograpy: Occlusion of the digital arteries proper of 2nd, 3rd and 4th finger of the hands. Electromyography Inferior Arts: normal. Superior Arts: bilateral suffering of the median nerve at the carpal tunnel. Biopsy of the hand cutis: Hyperkeratosis, acanthosis and papillomatosis of the skin. Arterial vases with signs of endothelioangiitis and aspecific inflammation. CONCLUSIONS: Even if acronecrosis of the superior limbs is a rare effect of the gemcitabine, we would recommend particular caution in the administration of this drug in patient with known autoimmune disorders.

[Early diastolic sound in a patient with hepatocarcinoma]. / Un tono aggiunto protodiastolico in un paziente affetto da epatocarcinoma.

On physical examination an early diastolic sound is usually associated with mitral stenosis, prosthetic mitral valve replacement and chronic constrictive pericarditis. In case of an atrial myxoma, an early diastolic sound can be usually heard due to movement of the tumor towards the tricuspid valve (tumor plop). The following case report shows an example in which an early diastolic sound was heard in a patient presenting with a hepatocellular carcinoma. This sound was due to the presence of a thrombus that originated from the inferior vena cava and invaded the right atrium up to the tricuspid valve. It was thus similar to an atrial myxoma and produced a tumor plop.

Polyclonal expansion of CD3(+)/CD4(+)/CD56(+) large granular lymphocytes and autoimmunity associated with dysregulation of Fas/FasL apoptotic pathway.

Evidence is accumulating regarding CD95/CD95 ligand (Fas/FasL) pathway dysregulation in clonal diseases of the lymphohaemopoietic lineages. According to these observations, it has been proposed that this defect may represent one of the mechanisms of tumour progression. In large granular lymphocyte (LGL) leukaemia, dysregulated apoptosis may represent a key event in the development of malignancy and autoimmunity. This case report describes dysregulation of the Fas/FasL pathway in a chronic polyclonal expansion of CD3(+) LGLs associated with numerous serological immune abnormalities.

[Transrectal ultrasonography in the early diagnosis of prostate carcinoma: use of a new ultrasonography technique with endorectal probe]. / L'ecografia transrettale nella diagnosi precoce del carcinoma prostatico: utilizzo di una nuova manovra ecografica con sonda endorettale.

Seventy-80% of prostatic carcinoma develops in the peripheral gland. Transrectal ultrasound (TRUS) has the capacity to identify nodules or hypoechogenic areas in the peripheral zone, suspected to be carcinoma. We describe a new echographic technic with endorectal probe (target compression test), to study hypoechogenic areas or nodules in the peripheral gland, during TRUS examination. Thirty-three patients, aged 49-77 years, with prostatic peripheral hypoechoic lesion at transrectal ultrasound, were studied. All patients underwent prostatic biopsy. Ten of the 11 positive patients (non compressible lesion) at the target compression test resulted to be affected by adenocarcinoma. Only 3 of the 22 negative patients (compressible lesion) at the target compression test resulted to be affected by adenocarcinoma. Even if our data have to be confirmed by further studies, they suggest that the target compression test may be a useful complementary test, during TRUS, in the evaluation of hypoechogenic areas in the peripheral gland.

The synergistic effect of simultaneous addition of retinoic acid and vitamin D3 on the in-vitro differentiation of human promyelocytic leukemia cell lines could be efficiently transposed in vivo.

Both human cell lines HL-60 and AML-193 exhibit a myeloblastic and promyelocytic morphology, respectively, but may be regarded as bipotent leukemic precursors. They can be triggered to differentiate to either granulocytes or monocytes upon retinoic acid (RA) or 1,25-dihydroxyvitamin D (D3) addition, respectively. We have investigated the effect of combined addition of these chemical inducers on the in-vitro differentiation of both cell lines. RA and D3 added together exert synergistic effects on the in-vitro maturation of these myeloid cell lines. Interestingly, the additive effects were lost if the cells were incubated with the inducers added at sequential times. The synergistic effect could be transposed in vivo and could be clinically significant in the treatment of the promyelocytic leukemia. This clinical strategy may help to prevent retinoic acid resistance or to overcome it in patients relapsed after RA therapy and usually unresponsive to a reinduction therapy with RA alone.

Erythrocyte uroporphyrinogen decarboxylase activity: diagnostic value and relationship with clinical features in hereditary porphyria cutanea tarda.

A marked discrepancy between mild and late clinical features and a nearly complete absence of erythrocyte uroporphyrinogen decarboxylase activity (Ery-UROD activity) was observed in a case of inherited porphyria cutanea tarda. The entity and time of appearance of clinical features, the onset of clinical symptoms after exposure to contributing factors, the effectiveness of phlebotomies and heterozygosity of the mother alone for uroporphyrinogen decarboxylase (UROD) deficiency were typical for familial porphyria cutanea tarda (F-PCT), whereas the extremely low UROD activity was peculiar to hepatoerythropoietic porphyria (HEP). These observations indicate that: 1) Ery-UROD activity may not always be useful to discriminate between F-PCT and HEP; 2) Ery-UROD activity does not always correlate with clinical symptoms; 3) in inherited UROD deficiency, the genetic defect may be heterogeneous. Finally, the observed discrepancy may provide additional evidence for the existence of tissue-specific isozymes.

Combined vitamin D3/retinoic acid induction of human promyelocytic cell lines: enhanced phagocytic cell maturation and hybrid granulomonocytic phenotype.

Studies on the effect of retinoic acid (RA) and 1,25-dihydroxyvitamin (D3) on the differentiation of leukemic cells have provided insight into the cellular and molecular mechanisms underlying hematopoietic cell differentiation. We have evaluated the combined effect of these chemical inducers on the differentiation of HL-60 and AML-193 promyelocytic leukemia cell lines. Simultaneous RA+D3 addition potentiated leukemic cell maturation up to mature phagocytic cells. Interestingly, AML-193 cells induced with D3 and RA displayed a typical neutrophilic morphology while exhibiting properties specific to monocytic cells, e.g., high expression of CD14 membrane antigen, capacity to bind bacterial lipopolysaccharide, and monocytic-specific esterase activity; this hybrid granulomonocytic (GM) phenotype was not observed upon initial incubation with one inducer and later addition of the other. Parallel control studies were performed with purified normal GM progenitors, triggered by interleukin 3+GM-colony-stimulating factor (CSF) in FCS-rich or -free clonogenic culture, by GM-CSF+M-CSF in FCS-rich clonogenic culture, and by M-CSF in liquid suspension culture. The progenitors grown in the first condition generate exclusively G clones, even upon addition of D3 and/or RA. The progenitors grown in the second and third culture conditions generate either G and M clones (second culture condition) or a population of cells composed by a majority of monocytes (third culture condition); the D3 addition did not modify this differentiation pattern, whereas RA or RA+D3 addition elicited a marked inhibition of monocytic differentiation. These observations suggest that the development of a hybrid GM phenotype is restricted to the progeny of bipotent GM leukemic precursors.

HOXB gene expression and function in differentiating purified hematopoietic progenitors.

Intensive efforts have led to the development of methods for stringent purification of adult hematopoietic progenitor cells (HPCs), particularly from peripheral blood (PB). The purification procedure previously reported by our group (Science, 1990) provided a high HPC frequency, but yielded a low HPC recovery (< or = 5-10%). We therefore developed an improved purification methodology based on "potentiated" negative immunobead selection (Step IIIP) by addition of anti-CD45, -11a and -71 monoclonal antibodies (mAbs) to the previously utilized panel of mAbs. This simplified procedure consistently allows not only high level purification but also abundant recovery of early HPCs: the final Step IIIP cell population (0.95 x 10(6) cells/4 PB donors, mean value) features an 81% HPC frequency and a recovery of 45% of the initial HPCs. The purified HPCs bear the primitive HPC phenotype, i.e., they are consistently CD34+, largely CD33-/45RA-, and in part HLA-DR-/low/CD38-/low/Thy-1+. In optimized semi-solid culture, the purified erythroid/multipotent HPCs give rise to macroscopic colonies (10,000-150,000 cells/clone, > 0.5 mm size colonies). This purification methodology compares favorably with previously reported procedures in terms of combined HPC frequency and recovery: availability of a large number of highly purified, early HPCs will provide an experimental tool for analysis of the molecular/cellular basis of early hematopoiesis. We have investigated by reverse transcription-polymerase chain reaction (RT-PCR) the mRNA expression of homeobox B (HOXB) cluster genes in purified HPCs induced in liquid suspension culture to gradual erythroid or granulopoietic (largely eosinophilic) differentiation and maturation by differential growth factor (GF) stimulus. Only B3 is expressed in quiescent HPCs. After GF treatment B3 expression is enhanced in the initial 24 h and then through erythroid and granulopoietic differentiation and maturation. HOXB4 and B5 are induced at slightly later times and expressed through maturation in both lineages, while B6 is selectively induced in granulocytic differentiation. B2 is transiently expressed at low level in the granulopoietic pathway, while it is detected only in advanced stages of erythropoiesis; B7, B8 and B9 are essentially not detected. Functional studies were performed with antisense phosphorothioate oligomers to HOX mRNAs including: 1) anti-B3 oligomer (alpha-B3) treatment of purified HPCs induces a striking blockade of both erythroid and granulomonocytic colony formation, 2) alpha-B6 selectively and markedly inhibits granulomonocytic colony formation, 3) alpha-B4 and alpha-B5 cause a significant, less pronounced decrease of both colony types and finally, 4) alpha-B2 and alpha-B7, alpha-B9 exert little and no effect respectively.

PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3.

We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by high level PML-RAR alpha protein; indeed, Zn(2+)-treated MTPR9 cells incubated with RA plus D3 exhibited significant terminal monocytic maturation, comparable to that of cells treated with D3 alone or combined with RA in absence of Zn2+. Similar observations were made in NB4, a PML-RAR+ human acute leukemic line. As expected RA treatment of NB4 cells causes granulocytic differentiation. Interestingly, the cell line is only scarcely induced to mature monocytic cells by D3 or D3 plus TGF-beta 1 treatment, whereas it is effectively induced to monocytic maturation by combined treatment with D3 and RA. Accordingly, the rate of NB4 cell proliferation is only slightly affected by D3 or D3 plus TGF-beta 1 treatment, mildly inhibited by RA, and markedly decreased by D3 plus RA. These results indicate that in both U937 and NB4 cells high level PML/RAR alpha expression inhibits the monocytic terminal differentiation program triggered by D3 or D3 plus TGF-beta 1, whereas RA treatment effectively antagonizes this inhibitory PML-RAR alpha action and restores the D3 differentiative effect.

Stringently purified human hematopoietic progenitors/stem cells: analysis of cellular/molecular mechanisms underlying early hematopoiesis.

Analysis of the cellular/molecular basis of the early steps of hematopoietic proliferation and differentiation is hindered by the rarity of hematopoietic progenitors and stem cells (HP/HSC). The intensive efforts devoted to the development of purification methods for early HP and HSC, although initially largely unsuccessful, have recently provided a high level of HP/HSC yield and/or recovery. The methodology developed by our group, recently improved, provides not only virtually complete purification, but also abundant recovery of early HP/HSC such as colony forming units granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM), burst forming units erythroid (BFU-E), CFU granulocyte/macrophage (CFU-GM)/CFU blast cells (CFU-B), and long-term culture initiating cells (LTC-IC) from adult peripheral and cord blood (CB). We have also developed a serum-free liquid suspension culture for unilineage erythroid (E), granulocytic (G) or monocytic (M) differentiation of stringently purified HP/HSC. These culture systems allow sequential collection and cellular/molecular analysis of discrete populations of hematopoietic cells at a homogenous stage of differentiation specifically along a unilineage pathway. These experimental tools have been utilized to investigate cellular/molecular mechanisms underlying early hematopoiesis. The transcription factor (TF) GATA-1 is considered to be the "master" gene of erythropoiesis. In highly purified HP/HSC undergoing E or GM differentiation, GATA-1 expression is characterized initially by proliferation-dependent activation and at later stages by sustained expression in the E pathway and suppression in the GM pathway. Hypothetically, similar on/off switches of lineage-restricted TF may underlie the binary fate decisions of early HP differentiation. The expression and modulation of hematopoietic growth factor receptors (HGFR) in early hematopoiesis have been extensively analyzed. The results suggest a model of transactivation cascade for HGFR such as interleukin 6 receptor (IL-6R), IL-3R, GM colony stimulating factor receptor (GM-CSFR), and erythropoietin receptor (EpR), whereby each HGF upmodulates the R(s) for distal-acting HGF(s). Finally, we have investigated the effect of HGF on reactivation of hemoglobin F (HbF) in clonogenic or liquid suspension serum-free culture of purified adult HP. The results suggest that c-kit ligand (KL) plays a key role in the reactivation of HbF synthesis in adult life, and IL-3/GM-CSF potentiate this effect at low KL level. The KL-induced HbF reactivation is seemingly related to an enhanced proliferation of early E progenitors in their differentiation pathway.

Transforming growth factor-beta potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines.

We have investigated the effects of 1,25-dihydroxyvitamin D3 (D3) and/or transforming growth factor (TGF)-beta on one monocytic (U-937) and two human promyelocytic (HL-60 and AML-193) leukemic cell lines. D3 addition induces a partial monocytic maturation of the cell lines, whereas TGF-beta treatment is largely ineffective. Combined treatment with TGF-beta and D3 causes terminal monocytic maturation, as evaluated both by assessment of a large spectrum of membrane Ag and by functional assays. Furthermore, sequential addition of the two inducers showed that pretreatment with TGF-beta 1 followed by incubation with D3, but not vice versa, induces monocytic maturation as effectively as simultaneous treatment with both agents. In liquid culture the proliferative activity of these cell lines is slightly decreased by D3 and virtually unaffected by TGF-beta, whereas combined treatment with D3 and TGF-beta induces a markedly potentiated inhibitory effect. Furthermore, TGF-beta/D3 treatment (but not D3 alone) elicits the expression of membrane CD14, FcRI, FcRII, CD11a, CD11b, CD11c, ICAM-1, and PECAM-1 Ag at a level comparable to that observed on normal human monocytes. It is noteworthy that several of these Ag play an important role in monocyte physiology (e.g., CD14 Ag mediates the binding of bacterial LPS to monocytes). Treatment with both TGF-beta and D3 (but not D3 alone) induces superoxide anions and H2O2 production similar to that of circulating monocytes. In semisolid culture, D3 and TGF-beta alone cause, respectively, a marked and slight loss of cloning efficiency of the cell lines, whereas their combined addition synergistically results in a complete loss of the cloning capacity. These findings suggest a physiologic role for TGF-beta in monocyte maturation. Furthermore, they may pave the way to the design of clinical protocols combining D3 and TGF-beta in the differentiation therapy of acute promyelocytic/myelomonocytic leukemia.

Cellular and molecular mechanisms in early hematopoietic differentiation.

Recently developed methodology allows virtually complete purification and abundant recovery of hematopoietic progenitors from human adult peripheral blood (PB) (1). We have recently utilized the population of stringently purified progenitors to investigate cellular and molecular mechanisms underlying the early steps of hematopoietic differentiation. Three aspects of these studies are briefly reported here.

Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level.

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.

Pure human hematopoietic progenitors: direct inhibitory effect of transforming growth factors-beta 1 and -beta 2.

TGF-beta 1 and TGF-beta 2 are effective inhibitors of hematopoiesis. We report that colony formation by pure peripheral blood CD34+CD33- BFU-E and CFU-GM (100 cells/dish) is effectively inhibited by both molecules, although TGF-beta 1 is up to 10-fold more potent than TGF-beta 2. Therefore, the effect of these molecules is apparently direct, rather than mediated by accessory cells. The maximal inhibitory activity of TGF-beta is exerted essentially at the early progenitor level, whereas BFU-E/CFU-GM primed for 48 h and IL-3, GM-CSF, and erythropoietin become insensitive to its action. In addition, [3H]TdR suicide experiments indicate that TGF-beta 2 blocks the IL-3-induced progression of early progenitors into the S phase of the cell cycle, whereas IL-6 and bFGF potentiate their entry into the mitotic process. Altogether, these results are compatible with the hypothesis that TGF-beta plays a relevant regulatory role in the homeostasis of early hematopoietic proliferation/differentiation.

IL-6/BSF-2 selectively stimulates the GO----S progression of CD8+ lymphocytes.

IL-6 preferentially promotes the DNA synthesis of human peripheral blood CD8+, rather than CD4+, lymphocytes in presence of PHA: this effect is observed in serum-free cultures of greater than 99% purified CD8+ lymphocytes. However, IL-6 is able to stimulate DNA synthesis of CD8+ lymphocytes triggered by a mitogenic anti-CD2 mAb, but not by anti-CD3 mAb: these results suggest that IL-6 selectively induces activation of CD8+ lymphocytes through the CD2 rather than the CD3 pathway. Limiting dilution analysis indicates that accessory cells are not required to mediate the action of IL-6 on CD8+ cells. Furthermore, this action is not blocked by addition of mAb neutralizing either IL-2 or IL2R, thus suggesting that IL-6 does not act via IL-2. CD8+ lymphocytes grown in the presence of PHA + IL-6 incorporate (3H)-thymidine to the same extent as those stimulated with PHA + IL-2, but do not increase in number until day 6 of culture. It is hence apparent that the stimulating activity of IL-6 on CD8+ lymphocytes is restricted to the GO----S phase progression, but does not lead to mitosis. IL-6 receptors are expressed on resting CD4+ and CD8+ lymphocytes: their expression is significantly enhanced on both activated CD4+ and CD8+ cells. Scatchard analysis of (125I)-IL-6 binding data showed the presence of high (Kd, 3 x 10(-10) M) and low (Kd, 6 x 10(-8) M) affinity IL6R on both lymphocyte populations. Similarly, mRNA encoding IL6R was detected in both CD4+ and CD8+ lymphocytes. Thus, our studies indicate that IL-6 directly and selectively stimulates the GO----S progression of CD8+ lymphocytes in the presence of mitogen and absence of IL-2: this phenomenon may be of interest for the elucidation of mechanisms activating cytotoxic T lymphocytes.

Constitutive expression and abnormal glycosylation of transferrin receptor in acute T-cell leukemia.

The expression of transferrin receptors (TrfRs) was investigated in acute T-cell leukemia (T-ALL) blasts at the molecular, biochemical, immunological, and functional level. TrfRs, although not detected on quiescent T-cells from normal adults, are constitutively expressed at high level on the blasts from all T-ALL patients and bind normally to transferrin. Their number is modulated by the intracellular iron level, but is independent of exogenous interleukin 2. They also exhibit immunological and biochemical abnormalities, in that: (a) they react preferentially with monoclonal antibodies (MAb) that recognize ligand-binding domains of TrfR (42/6 and 43/31), as compared to MAbs (B3/25, OKT9) that interact with the nonligand binding domains; (b) they have a reduced molecular weight, as compared to TrfR on normal thymocytes and activated T-lymphocytes: this phenomenon is apparently related to a defective glycosylation. It is noteworthy that expression of TrfR was not observed in a large series of other types of acute leukemias, i.e., pre-B, B, and myeloid leukemias, excluding erythroleukemias. The constitutive, high level expression of TrfRs on T-ALL blasts may play a key role in the stepwise progression of this malignancy and particularly provide a proliferative advantage to T-ALL blasts as compared to normal T-lymphocytes. Furthermore, indirect evidence suggests that the glycosylation defect of TrfR on T-ALL blasts contributes to their tumorigenic capacity.

Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation.

We have investigated the effect of iron on the expression of transferrin receptors (TrfRs) and ferritin chains in cultures of human peripheral blood monocytes maturing to macrophages. Monocyte-macrophage maturation is associated with a gradual rise of Trf-binding capacity in the absence of cell proliferation. At all culture times, treatment with ferric ammonium citrate induces a dose-dependent rise of the Trf-binding level as compared with nontreated cells. Scatchard analysis revealed that this phenomenon is due to an increase in receptor number rather than an alteration in ligand-receptor affinity. Biosynthesis experiments indicated that the rise in number of TrfRs is due to an increase of receptor synthesis, which is associated with a sustained elevation of the TrfR RNA level. The up-regulation of TrfR synthesis is specific in that expression of other macrophage membrane proteins is not affected by iron addition. Conversely, addition of an iron chelator induced a slight decrease of TrfR synthesis. The expression of heavy and light ferritin chains at RNA and protein levels was markedly more elevated in cultured macrophages than in fresh monocytes, thus suggesting modulation of ferritin genes at transcriptional or post-transcriptional levels. Addition of iron salts to monocyte-macrophage cultures sharply stimulated ferritin synthesis but only slightly enhanced the level of ferritin RNA, thus indicating a modulation at the translational level. These results suggests that in cultured human monocytes-macrophages, iron up-regulates TrfR expression, thus in sharp contrast to the negative feedback reported in a variety of other cell types. These observations may shed light on the mechanism(s) of iron storage in tissue macrophages under normal conditions and possibly on the pathogenesis of diseases characterized by abnormal iron storage.

Fluctuations of plasma beta 2-microglobulin, soluble interleukin 2 receptor and interferon-gamma concentrations after adoptive immunotherapy with high-dose interleukin 2 and lymphokine-activated killer cells.

We report the serum levels of soluble interleukin 2 receptor (sIL2R), beta 2-microglobulin (beta 2-M) and interferon-gamma (IFN-gamma) in patients undergoing adoptive immunotherapy with rIL2 and lymphocyte-activated killer (LAK) cells. Our results indicate that rIL2 induced a marked increase of the serum concentration of these markers, although this increase varied considerably for different individuals. Parallel studies with the same patients also showed a marked rise in the number of IL2R+ lymphocytes: the IL2Rs expressed on these cells were mainly of the "low affinity" type. We suggest that evaluation of these markers may allow the monitoring of immune system activation induced by rIL2 in patients undergoing adoptive rIL2 and LAK cell immunotherapy.