Role of interleukin-2 in regulating lymphocyte activation and recirculation.
Explore the source record for details and available documents.
CD4 Antigens↗
Biomedical subjects
C Rugarli
Publications and source records attributed to C Rugarli.
Signal transduction in human tumor infiltrating lymphocytes.
In the present study we demonstrate that the CD28 activation pathway was functional in human tumor infiltrating lymphocytes (TIL), as it could induce a strong proliferation. On the other hand, a mitogenic combination of anti-CD2 monoclonal antibodies (MoAb) induced a slight proliferation of TIL isolated from lung but not from renal cell carcinoma (RCC). It is to note that CD28 triggering led to calcium mobilization, whereas stimulation via CD2 did not. Moreover, in most cases no synergistic effect between CD2 and CD28 activation pathways could be observed. Phenotypic analysis showed that freshly isolated TIL were mostly CD3+, LAM1+ and CD45RO+. Upon stimulation with anti-CD28 MoAb, the majority of cells lost LAM1 antigen and coexpressed both high (CD45RA) and low (CD45RO) molecular weight isoforms of CD45 molecule. By contrast, among CD2-activated TIL, a small fraction was LAM1+ and less than 10% coexpressed CD45RA and CD45RO antigens. Noteworthy, the CD45 molecule could regulate the CD28-induced calcium mobilization, as demonstrated by cross-linking of CD45RO, but not CD45RA, isoforms before challenging TIL with anti-CD28 MoAb.
Antigens, Differentiation, T-Lymphocyte↗
Unusual expression and localization of heat-shock proteins in human tumor cells.
It has been suggested that members of HSP families represent the surface target of immune responses leading to tumor rejection in mice. Here we report that tumor cells, compared with normal cells, constitutively expressed 2- to 10-fold higher levels of intracellular HSP90. Moreover, in the absence of environmental stress, 2 lines (out of 6) expressed the "inducible" HSP72, which was also detectable in fresh tumor cells. HSP72 expression was not regulated during the cell cycle, in contrast with what has been observed with normal cells. Both HSP90 and HSP72 proteins exhibited a heterogeneous pattern of intracellular distribution in most cells, HSP72 being confined mainly to the nuclear compartment. Finally, we could detect both HSP90 and, to a lesser extent, HSP72 (that are generally believed to be located intracellularly) at the surface of some tumor cell lines. We conclude that tumor cells differ from normal cells in their pattern of HSP expression; this might imply a role of HSPs in eliciting an immune response against cancer.
Cell Cycle↗
Signalling in human tumour infiltrating lymphocytes: the CD28 molecule is functional and is physically associated with the CD45R0 molecule.
The CD28 T cell activation pathway was functional in human tumour infiltrating lymphocytes (TIL) and can induce strong proliferation, lymphokine release and calcium mobilisation. Conversely, TIL responded poorly to stimulation via CD2, and CD28 did not synergise with CD2, which is at variance with that observed using peripheral lymphocytes from the same patients. On stimulation with anti-CD28 the monoclonal antibody, most TILs, which were CD3+, CD28+ and CD45R0+ at the beginning of culture, co-expressed both high (CD45RA) and low (CD45R0) molecular weight isoforms of CD45. CD28 was associated with the CD45R0 isoform at the cell surface of activated TIL, as demonstrated by immunoprecipitation and immunoenzymatic assay. Thus CD28 can substitute for CD3 in TIL leading to the expansion of functional lymphocytes and to the amplification of antitumour immune response.
Antibodies, Monoclonal↗
Antigen-receptor complex stimulation triggers protein kinase C-dependent CD11a/CD18-cytoskeleton association in T lymphocytes.
Although it is well accepted that intercellular adhesion involving the CD11a/CD18 (LFA-1) complex is critical in a wide array of T cell-dependent processes, recent demonstrations of an LFA-1 high avidity state, induced by triggering the T cell receptor (TCR) complex, has raised questions about the intracellular signals generated and molecular events leading to effective cell coupling, as well as their orderly sequence. In this study, we assessed the effects of T cell activation on the actin-based cytoskeleton, and LFA-1, as well as their interaction. Crosslinking the TCR complex with anti-CD3 mAb resulted in actin polymerization and colocalization with LFA-1, as detected by fluorescence microscopy. This association was confirmed by immunoprecipitating LFA-1 from the detergent insoluble, cytoskeletal-associated membrane fraction after TCR crosslinking. These consequences were inhibited by the protein kinase C (PKC) inhibitor staurosporine or by PKC desensitization, as was a transient CD11a hyperphosphorylation, induced by monoclonal anti-CD3. Furthermore, a small percentage of beta 2-deficient T cells maintained the ability to rearrange the cytoskeleton in response to TCR complex activation, with F-actin-VLA4 colocalization. These results provide evidence that the important consequences of TCR-induced signal transduction include a PKC-dependent cytoskeletal rearrangement, involving an association between leukocyte integrins and F-actin. We discuss the implications of these findings with respect to effective T cell functions.
Actins↗
Autoimmune thyroiditis following interleukin-2 and LAK cell therapy for metastatic renal cell carcinoma: correlation with tumor regression.
A 63-year-old woman receiving recombinant interleukin-2 (rIL-2) + lymphokine activated killer cells for metastatic renal cell carcinoma developed autoimmune thyroiditis with clinical hypothyroidism and high titer anti-thyroglobulin and anti-microsomal antibodies. The onset of thyroid dysfunction was associated with tumor regression and resulted in complete response at the end of the treatment. Cytologic and cytofluorimetric studies on thyroid tissue showed two distinct populations, mainly consisting of small lymphocytes and large thyrocytes, and the latter expressed MHC class II antigens. After completion of rIL-2 treatment, hypothyroidism gradually decreased until resolution; complete tumor remission lasted 18 months. Mechanisms underlying the association between autoimmune thyroiditis and cancer regression are discussed.
Carcinoma, Renal Cell↗
Recombinant interleukin-2 and lymphokine-activated killer cells in renal cancer patients: II. Characterization of cells cultured ex vivo and their contribution to the in vivo immunomodulation.
Peripheral blood mononuclear cells, obtained from patients with renal cell cancer and cultured ex vivo, exhibit high natural killer (NK) and lymphokine-activated killer (LAK) activity (also against allogeneic fresh tumour cells), which is transcribed into the hosts' immune status after reinfusion. Phenotypic analysis shows a slight increase in the percentage of CD56+ and CD8+ lymphocytes, while CD4+ lymphocytes decrease slightly. As a sign of activation an increase of cells expressing DR and CD25 antigens is observed. At the peripheral blood level, mononuclear cells show an increase, compared to basal values, of NK and LAK activity, especially at the end of the first infusion cycle. Phenotypic analysis of the patients' PBMC shows a decrease of CD3+CD4+ T lymphocytes and an increase of NK cells (CD3-CD56+CD16+) and of cells expressing activation markers (DR and CD25), particularly evident by the end of the second infusion cycle. Finally, in addition to the changes induced by IL-2 alone, reinfusion of incubated cells results in an activation of CD56+ and LeuM3+ cells.
Antigens, CD↗
Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sjögren syndrome.
We report an unusual case of chronic bilateral dacryo-adenitis in 10-year-old identical twin sisters. Both girls presented with bilateral lacrimal gland enlargement and developed moderate xerophthalmia and keratitis. Both the lacrimal and minor salivary gland biopsies showed a non-granulomatous inflammatory infiltration of mono-nuclear cells. All granulomatous diseases and neoplasms could therefore be ruled out and only Sjögren syndrome and very few other forms of chronic dacryo-adenitis remained as possible diagnoses. Both patients and their parents were evaluated for auto-antibodies. Very low titres of smooth muscle antibodies were found in one, antinuclear antibodies in two and anti-dsDNA antibodies in all four members of the family. Even though the titres of antinuclear and anti-dsDNA antibodies increased in one of the sisters, both patients did not develop any sign or symptom of a systemic connective tissue disease. During the 6 years' follow up, both patients showed persistent tarsal gland enlargement but no other symptoms apart from a moderate xerophthalmia and occasional mild keratitis.
Biopsy↗
Clinical outcome and follow-up of patients with renal damage in microscopic polyarteritis. Personal data.
Explore the source record for details and available documents.
Adult↗
Meperidine in detoxification of hospitalized heroin addicts.
Forty-six heroin abusers were hospitalized and treated with meperidine either alone or in association with clonidine. Meperidine was given orally in rapidly decreasing doses according to three different schedules. The majority of patients (87%) successfully completed the detoxification program. The best meperidine starting posology was 200 mg four times daily, which allowed stoppage of the opioid treatment after gradual reduction of the daily dose in a mean time of 9.5 days. Association with clonidine was not proven to be useful. This study shows that meperidine can be effectively used in rapidly decreasing doses in the pharmacological detoxification treatment of hospitalized heroin addicts.
Administration, Oral↗
Selective lysis of the autologous tumor by delta TCS1+ gamma/delta+ tumor-infiltrating lymphocytes from human lung carcinomas.
Two distinct non-overlapping populations of TcR1+ (gamma/delta) T cells have been described: the first, bearing the disulfide-linked gamma/delta heterodimer, is predominant in the peripheral blood; the second, expressing the non-disulfide-linked form of TcR1, is mostly confined to epithelial tissues (lung, gut, skin). TcR1+ lymphocytes may be cytotoxic and could be involved in anti-tumor immunity, especially against tumors at epithelial sites. Freshly derived tumor-infiltrating lymphocytes (TIL) obtained from two patients with lung cancer were enriched in CD3+WT31- cells. The percentage of this subset substantially increased upon culture in the presence of interleukin 2. These cells were TcR1+ as demonstrated by immunofluorescence and immunoprecipitation. In one case only 40% of this population reacted with delta TCS1 mAb, that recognizes the non-disulfide-linked form of TcR1, and co-expressed the CD8 antigen. Cultured TcR1+ TIL were able to kill fresh autologous tumor cells, K-562 and, to a lesser extent, some natural killer-resistant cell lines and allogeneic lung tumor cells in 4-h 51Cr-release cytotoxicity assays. The fractionated delta TCS1+ TIL lysed only autologous tumor cells and K-562, whereas the lytic activity against all the other targets was confined to the delta TCS1- subset. Moreover, the autotumor cytotoxicity was inhibited by anti-HLA class I but not by anti-CD1c or anti-LFA-1 mAb, suggesting that killing of the autologous tumor cells and non-major histocompatibility complex-restricted cytotoxicity are mediated by different mechanisms.
Antibodies, Monoclonal↗
Recombinant interleukin-2 and lymphokine-activated killer cells in renal cancer patients: I. Phenotypic and functional analysis of the peripheral blood mononuclear cells.
The efficacy of recombinant interleukin-2 (rIL-2) or rIL-2 plus lymphokine-activated killer (LAK) cells in cancer therapy has been demonstrated by several groups both in experimental models in animals and clinical trials in humans, but their effects in vivo have yet to be clarified. Starting February 1988, we have treated 12 patients affected by advanced renal cancer with rIL-2 + LAK cells according to an open, non-randomized, phase II trial. Immediately before each rIL-2 infusion and during the last day of infusion, immunological tests were performed on the patients' peripheral blood mononuclear cells. During rIL-2 infusion we have observed a slight increase of the spontaneous cell proliferation and of natural killer (NK) and LAK activity; phenotypic analysis showed a significant decrease in the CD4+ T-lymphocyte subset, both in percentage and in absolute number. Conversely, before each cycle CD4+ cells increased when compared to basal values. No significant variations were observed in the CD8+ T-lymphocyte subset. Furthermore, a significant increase of the NK cells (CD3- CD56+ CD16+) was evident during rIL-2 infusion.
CD4 Antigens↗
LAK1: a novel leucocyte differentiation antigen shared by lymphoid and endothelial cells.
Lymphokine activated killer (LAK) cells have been utilized as a useful tool in cancer adoptive immunotherapy. The lineage origin of this population has always been controversial since it shares phenotypic markers with both myelomonocytic cells and T lymphocytes. Recently we described a new monoclonal antibody (MoAb), termed LAK1, which recognizes a 120 Kd surface molecule expressed on human large granular lymphocytes (LGL) and LAK precursors and effectors. LAK1 MoAb defines two different populations of positive cells amongst peripheral lymphocytes: the first subset (20%), represented by brightly stained cells, belongs to the non T-LGL population, whereas the second subset (30%) displays low fluorescence intensity and was partially composed of T lymphocytes. More interestingly, LAK1 is shared by some other cell types, such as monocytes and vascular endothelial cells. Immunohistochemical staining performed on muscle, endometrium and lymphoid or other non lymphoid tissues shows that LAK1 antigen is selectively expressed by the reticuloendothelial system.
Antibodies, Monoclonal↗
Identification of a new surface molecule expressed by human LGL and LAK cells production of a specific monoclonal antibody and comparison with other NK/LAK markers.
Recently we described a new monoclonal antibody, termed LAK1, which recognizes a 120-kDa surface antigen that is expressed on virtually all LGL and LAK precursors and effectors. In the present study we describe a second mAb, termed LAK2, which was derived against cloned LAK cells. The LAK2 mAb, similar to the LAK1 mAb reacts with a subset of peripheral blood lymphocytes which includes the precursors of LAK cells. In addition, among IL2-activated peripheral lymphocytes, this antibody defines cells displaying LAK activity. The expression of the LAK2 molecule on PBMC was analyzed by two-color cytofluorometric analysis in comparison with the expression of both T cell and LGL markers. We show that most resting LAK2+ cells lack surface expression of CD3, whereas nearly 60% express CD2 antigen. Moreover, all CD16+ and CD56 (NKH1)+ lymphocytes coexpressed both LAK2 and LAK1 antigens. Morphological analysis of LAK2+ lymphocytes indicated that the majority of these cells was represented by LGL. Thus the expression of the LAK2 molecule on LGL-enriched populations was compared by two-color cytofluorometric analysis to that of other known LGL markers such as CD16, CD57 (HNK1), and LAK1. Most LGL coexpressed LAK1, LAK2, CD16 and CD57 antigens Finally, the surface molecule recognized by LAK2 mAb is composed of two chains with apparent molecular masses of approximately 110 and 140 kDa.
Animals↗
Metastatic renal cell cancer treated with low-dose interleukin-2. A phase-II multicentre study.
Explore the source record for details and available documents.
Adult↗
Essential mixed cryoglobulinemia: a report on 14 cases.
Fourteen cases of Essential Mixed Cryoglobulinemia (EMC) are described in this report. Clinical and laboratory manifestations in our patients were similar to those previously reported in literature, although involvement of the peripheral nervous system was much more prevalent in our series. We suggest that peripheral neuropathy should be systematically searched in EMC patients.
Adult↗
Progress in therapy of renal cell cancer.
Explore the source record for details and available documents.
Carcinoma, Renal Cell↗
NK cell activity and monocyte dysfunctions in a patient with common variable hypogammaglobulinemia.
A 57-year-old man with a history of recurrent infections from the age of 50 was hospitalized with a diagnosis of common variable hypogammaglobulinemia (CVH). Immunological studies revealed a severe reduction of circulating immunoglobulins of all classes. Immunophenotyping of peripheral blood mononuclear cells (PBMC) with monoclonal antibodies, revealed normal values of total B and T cells with CD4/CD8 ratio sharply reduced (0.35) as compared to normal (1.6) because of an increase of CD8 and a decrease of CD4 cells. The surface expression of IL-2 receptor was normal. Natural cytotoxic and phagocytic system presented several abnormalities: a deep impairment of NK activity was found in spite of a normal number of NK cells, as ascertained by Leu 19 and B73.1 monoclonal antibodies. The defective NK activity was not restored by interferon alfa, but was normalized by recombinant IL-2. Phagocytic function, as defined by zymosan-stimulated O2- production was almost absent. The involvement of natural cytotoxic and phagocytic systems in CVH has been rarely reported; the possible causative role of a chronic viral infection (Epstein-Barr virus?) is discussed, on the base of anamnesis.
Antibodies, Monoclonal↗