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Biomedical subjects

G Pawelec

Publications and source records attributed to G Pawelec.

At least 145 records · Page 8Linked to original sources
PubMed1989

In vitro generation of IFN-gamma in relationship to in vivo concentration of IgE and IgG subclasses and Fc epsilon Rl/CD23 positive circulating lymphocytes in patients with severe atopic dermatitis (AD).

In fifteen patients with severe atopic dermatitis (AD) and ten healthy controls we investigated the in vitro generation of IFN-gamma and analysed the number of Fc epsilon RL/CD23 (low affinity Fc receptor for IgE) positive lymphocytes. We found a significantly impaired capacity to secrete IFN-gamma after PHA-stimulation compared to controls in a significant proportion of patients. Serum IgG4 levels in patients were higher compared to controls. A significant portion of lymphocytes bearing the low affinity Fc receptor for IgE (CD23) was observed with the moab Tü1 in patients. Lymphocytes from healthy donors were completely negative or less than 2% positive for Tü1. Despite small numbers of patients a significant correlation was found between IFN-gamma generation in vitro and IgE serum concentration in patients, whereas the IFN-gamma generation and IgG4 concentration were negatively correlated in the patient group. The number of Fc epsilon RL/CD23 positive lymphocytes in patients was positive correlated with the serum IgG4 and IgE concentration and negative correlated with IFN-gamma generation in vitro. Our data suggest that a possible dysregulation of IFN-gamma, Interleukin 4 or other lymphokine production may be related to increased IgE and IgG4 production.

Adolescent↗
PubMed1989

Cytokine release from cultured peripheral blood mononuclear cells of patients with severe atopic dermatitis.

Peripheral blood mononuclear cells (PBMC) from 14 patients with severe atopic dermatitis (AD) and 11 healthy donors were tested for their capacity to produce tumour necrosis factor-alpha (TNF-alpha) after PHA stimulation and compared with their in vitro production of interferon-gamma (IFN-gamma). The mean TNF-alpha production in AD patients did not differ vis-à-vis controls. However, a significant portion of patients with AD which was defective in generating IFN-gamma in vitro showed in addition significantly a decreased production of TNF-alpha. No correlation could be found between TNF-alpha and neopterin production in either group, whereas there was a close overall correlation between the amount of TNF-alpha and IFN-gamma detectable in culture supernatants of patients and controls. Furthermore, a significant correlation was found between TNF-alpha and IFN-gamma generation in vitro and serum IgE concentration in AD. Based on cytokine production in vitro and IgE concentration in vivo, patients with severe AD could be divided into two groups. Furthermore, 3 AD patients with normal IFN-gamma generation and low serum IgE concentration but suffering from eczema herpeticum formed a subgroup which showed an increased TNF-alpha production in vitro. The data suggest alterations in cytokine production in a subgroup of patients with AD which bear a reciprocal relationship to abnormal IgE regulation.

Biopterins↗
PubMed1988

Lymphoma-specific T- and B-cell responses suggest the involvement of HTLV-I in virus-non-productive lymphomas of a married couple.

In a married couple, a T-cell and a B-cell lymphoma occurred at the same time in the husband (FR) and wife (FE), respectively. Serum antibodies of patient FE with less advanced tumor progression specifically recognized HTLV-I-related envelope precursor molecules of 66-68 kDa molecular mass on HTLV-I-infected T- and B-cell lines, but not on HTLV-II or HIV-infected cells. In addition, in vivo-activated CD8+ T-cell lines (TCL) from this patient specifically lysed autologous B-lymphoma cells, T-lymphoma cells from the husband (FR), as well as the HTLV-I-transformed MT2 T-cell line. All positive target cells shared an HLA-class-I cross-reactive determinant identified by the alloantiserum WER127. On a clonal level, the specificity of the cytotoxic T-cell response was unequivocally distinguishable from classical natural-killer-like cytotoxicity. Results imply the involvement of a common inductive agent in the manifestation of malignant lymphoma in both patients (FR and FE). Since antibodies from cases with classical HTLV-I-induced adult T-cell leukemias (ATLL) did not bind antigens on cells of either lymphoma (FR or FE) and active virus production was not demonstrable under various different conditions, these results argue against HTLV-1 itself being the transforming agent. However, humoral and cellular immune responses of one patient (FE), in addition to de novo HLA-class-1 antigen expression of both patients, are nonetheless consistent with the involvement of viral infections(s). These were responsble for the expression of HTLV-1-characteristic envelope determinants of the malignant progeny of respective T- and B-cell origin.

Aged↗
PubMed1988

Human leukocyte antigen-DP in leukemia.

Human leukocyte antigen-DP (HLA-DP) typing was performed on patients with chronic myelogenous leukemia (CML, n = 44), acute nonlymphoblastic leukemia (ANLL, n = 34), or acute lymphoblastic leukemia (ALL, n = 41). Frequencies of DPw alleles in CML and ANLL patients were not significantly different from 254 controls, except that in ANNL DPw1 was absent. This was most likely due to the concurrent absence of DR3 with which DPw1 is in linkage. In contrast, in ALL, frequencies of DPw2 and DPw5 were significantly increased (corrected P less than 0.05, relative risk (RR) = 2.19 and corrected P less than 0.01, RR = 6.92, respectively). This was not due to linkage with DR. The frequency of DPw1 also tended to be reduced, but this was not caused by a similar decrease of DR3 in ALL. These results, therefore, demonstrate both positive and negative associations between major histocompatibility complex (MHC) gene products which are in only very weak linkage with the rest of HLA, and acute lymphocytic, but neither acute nor chronic myelogenous, leukemias. The HLA-DP region could thus contain long sought-after genes influencing susceptibility and resistance to leukemogenesis.

Alleles↗
PubMed1988

DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity.

A set of T cell clones (TCC) isolated from HLA-DR-, Dw-, DQ-matched allogeneic MLCs was found to proliferate autonomously when stimulated with cells carrying a wide range of class I or II specificities. This apparently unrestricted proliferation was relatively weak, and only low levels of IL-2 were present in the supernatants of stimulated cells. Autologous as well as allogeneic PBMC and B lymphoblastoid cell lines (B-LCL) were capable of stimulating such clones, which were also restimulated by suppressive, but not by helper, TCC. Moreover, such clones displayed the unusual property of autostimulation. mAb inhibition experiments suggested that class II- or class II-restricted antigens were involved in stimulation. Thus, certain "broad" mAbs (TU39, SG520) reacting with multiple locus products inhibited activation of these reagents, but none of those reacting more specifically with DR (TU34, TU37, L243, Q2/70, SG157), DQ (TU22, SPV-L3, Leu 10), or DP (B7/21), or mixtures of these mAbs, were able to do so. Evidence from sequential immunoprecipitation experiments suggested that mAb TU39 bound class II-like molecules other than DR, DQ, and DP on TCC and B-LCL, and it is therefore proposed that such putative novel class II-like molecules may carry the stimulating determinants for these autoreactive clones. DY-reactive clones lacked helper activity for B cells but mediated potent suppressive activity on T cell proliferative responses that was not restricted by the HLA type of the responding cells. Suppressive activity was induced in normal PBMC by such clones, as well as by independent suppressive clones, which was also inhibited only by mAb TU39. These findings lead to the proposal that DY-reactive autostimulatory cells may constitute a self-maintaining suppressive circuit, the level of activity of which would be regulated primarily by the availability of IL-2 in the microenvironment.

Antibodies, Monoclonal↗
PubMed1988

Division of human helper T cells into two sets on the basis of the induction of anti-tumor cytotoxicity by phorbol ester and calcium ionophore.

Fourteen noncytotoxic human helper T cell clones were examined for autocrine proliferative responses and cytotoxicity to tumor cells after stimulation with 12-O-tetradecanoylphorbol 13-acetate (TPA) and ionomycin (Io). Although all clones responded to alloantigen, they could be divided into two groups based on their proliferative response or lack of it to TPA/Io. Nonresponders could not be converted to responder status by addition of interleukin (IL) 1 or indomethacin to the cultures. Responder status did not correlate with any of the following properties of the clones: originating donor, recognitive specificity, B cell helper activity, proliferative response to IL 2 or 4, lymphokine secretory capacity or density of expression of antigen receptors, CD4 or HLA class II molecules. Responder status did, however, correlate with the ability of TPA/Io to induce major histocompatibility complex-unrestricted cytolytic activity directed towards natural killer-resistant tumor cells. These results divide human helper cells into two types on the basis of induction of anti-tumor cytotoxicity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Cellular immunological defects of chronic myelogenous leukaemics: partial dependence on busulphan therapy.

The PBMC from treated (n = 10) and untreated (n = 7) chronic phase CML patients were examined for their functional expression of helper cell-stimulating class II products, HLA-DR and -DP, and for their ability to induce suppression in normal PBMC. Although DR and DP were found to be functionally expressed in both groups of patients, a dysregulation of suppression induction was found in treated but not in untreated patients. Furthermore, the patients demonstrated a virtual absence of NK activity and severely depressed LAK activity which was equally striking in both treated and untreated patients and did not seem to be related to the presence of active suppression of cytotoxicity. Such defects in chronic phase CML patients may be relevant to the progression of their disease. Moreover, at least one of the cellular immunological defects, induction of suppressive cells, was not intrinsic to the disease, but appeared to be chemotherapy related.

Antigens, Differentiation↗
PubMed1988

Regulation of allospecific suppressive cell generation in vitro.

Control of the generation of suppressive cells (SC) in allogeneic mixed lymphocyte cultures (MLC) has been re-investigated. Cells taken from 3-6 days old ("early", e-MLC) suppressed lymphocyte proliferative responses when transferred to a second MLC. Suppression was not allospecific, nor restricted to the autologous responder. In contrast, cells from MLC 7-10 days old ("late", l-MLC) mediated weak but specific suppressive activity, which was HLA-restricted. Addition of early MLC cells (e-MLC1) to a second MLC (MLC2), blocked the further generation of non-specific suppressive activity in that MLC, suggesting the presence of downregulatory components for SC generation. Nonetheless, the generation of allospecific suppression in late MLC2 (l-MLC2) was enhanced rather than inhibited under these conditions. In separate experiments, a T cell clone (TCC) was isolated which mimicked the action of e-MLC cells on SC generation, namely, down-regulation of non-specific but amplification of specific SC generation. This clone carried the "alternative" tau/delta T cell receptor. Thus, tau/delta+ "antisuppressor" regulatory cells may have a role in the establishment and maintenance of allograft tolerance.

Histocompatibility Antigens Class II↗
PubMed1988

Cyclosporin A blocks the generation of alloindifferent but not of allospecific suppressive cells.

The induction of alloantigen-indifferent, MHC unrestricted suppressive cells (SC) early on in human mixed lymphocyte culture (MLC) or after stimulation with suppressive T cell clones was blocked in a dose-dependent fashion by cyclosporin A (CsA). This was not prevented by the addition of the following defined lymphokines: interleukin (IL) -1, -2, -4, -5, interferon-tau or GM-CSF. The addition of MLC-conditioned medium as a source of multiple lymphokines including IL-3 also failed to reconstitute suppressive activity in the presence of CsA. In contrast, the development of allospecific, HLA-restricted SC in the same CsA-blocked MLC was not prevented or was even enhanced. These results confirm that CsA 'spares' specific SC induction late in MLC, but show that it prevents induction of non-specific suppression earlier in MLC by a mechanism presumably unrelated to blocking the secretion of interferon-tau or IL-1 to IL-5.

Cyclosporins↗
PubMed1988

HLA-DP in rheumatoid arthritis.

Frequencies of HLA-DR, Dw and DPw specificities were compared between rheumatoid arthritis (RA) patients, Felty's syndrome (FS) patients and normal controls. It was confirmed that the frequency of DR4 was increased in RA patients (54% (n = 111) vs 23% (n = 272), relative risk (RR) = 3.98, P less than 0.001). Cellular typing showed a highly significant increase in HLA-Dw14 in the entire RA population (17% (n = 32) vs 2% (n = 242), RR = 11.90, P less than 0.001), and a tendency towards an increase of HLA-Dw14 in DR4+ RA patients compared to DR4+ controls (28% (n = 32) vs 11% (n = 47), RR = 3.29, P less than 0.05). Regarding DPw specificities, the only significance was for a negative association with DPw3 (13% vs 22% (n = 254), RR = 0.51, P less than 0.05), with an additional tendential decrease of DPw1 (11% vs 19%, RR = 0.53, not significant (NS]. The decrease of DPw3 was more marked in DR4- RA patients (RR = 0.33, P less than 0.05) than in DR4+ RA patients (RR = 0.69, NS). In FS patients, 96% of whom were DR4+, decreased DPw1 was very marked, whereas the frequency of DPw3 was unaltered compared to DR4+ normals. These alterations in frequencies were not caused by linkage disequilibria between HLA-DR and -DP alleles. Thus, taken together, these data suggest that, in the presence of the major DR4-associated "susceptibility" gene(s) for RA, DPw1 may have "protective" effects, whereas in the absence of DR4, the presence of DPw3 has significant "protective" activity.

Arthritis, Rheumatoid↗
PubMed1988

Immunoglobulin E and immunoglobulin G subclass distribution in vivo and relationship to in vitro generation of interferon-gamma and neopterin in patients with severe atopic dermatitis.

In vitro interferon-gamma (IFN gamma) and neopterin generation by peripheral blood mononuclear cells (PBMC) from 15 patients with severe atopic dermatitis (AD) and 10 healthy controls was investigated. A significant proportion of patients had an impaired capacity to secrete IFN gamma after phytohemagglutinin (PHA) stimulation in vitro and therefore IFN gamma production was significantly lower compared to controls. Neopterin generation in vitro did not differ significantly from that of controls and no correlation between in vitro IFN gamma and neopterin production could be observed in either group. Analysis of serum IgG subclass distribution showed that patients with AD. had increased IgG4 serum concentrations while IgG1, IgG2 and IgG3 levels did not differ significantly from those of controls. Surface marker analysis revealed increased numbers of CD23+ lymphocytes in patients with AD which was positively correlated with the serum IgG4 and IgE concentration. Furthermore, a significant correlation was found between IFN gamma generation in vitro and IgE and IgG4 concentration in vivo in AD. The data suggest that a possible dysregulation of IFN gamma, interleukin-4 or other lymphokine interleukin-4 or other lymphokine production may be related to increased IgE and IgG4 production and seems to be an important factor in the pathogenesis of AD.

Adult↗
PubMed1988

"Tolerization" of human T-helper cell clones by chronic exposure to alloantigen: culture conditions dictate autocrine proliferative status but not acquisition of cytotoxic potential and suppressor-induction capacity.

Induction of clonal anergy in T-helper (Th) cells may have a role in regulating immune responses. A model system for studying Th cell tolerization at the clonal level in vitro could be useful for investigating the mechanisms involved. Accordingly, alloreactive helper cells were maintained in culture with interleukin 2 (IL 2) by intermittent stimulation with specific antigen. Regardless of the frequency of antigen stimulation, clones of age less than ca. 35 population doublings (PD) were found to undergo antigen-specific autocrine clonal expansion in the absence of exogenous IL 2. Such young clones (designated as phase I) could therefore not be "tolerized" by frequent exposure to antigen. In contrast, most clones of age greater than ca. 35 PD could be tolerized by frequent exposure to antigen (designated as phase II clones). Their autocrine proliferation was then blocked, although they still recognized antigen specifically as shown by their retained ability to secrete interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF). The mechanism of response failure involved both an inability to upregulate IL 2 receptors in the absence of exogenous IL 2, as well as an inability to secrete IL 2. These defects were not overcome by stimulation with mitogens or calcium ionophore and phorbol esther in place of alloantigen. T-cell receptor, alpha, beta, and gamma-chain gene rearrangements remained identical in phase I and phase II clones. Tolerization of phase II clones could be avoided by increasing the period between antigen exposures. Despite this, whether or not phase II cells were capable of autocrine proliferation, they were found to have acquired the novel function of inducing suppressive activity in fresh lymphocytes. Suppressor-induction was blocked by the broadly reactive MHC class II-specific monoclonal antibody (moAb) TU39, but not by moAb preferentially reacting only with HLA-DR, DQ, or DP. Sequential immunoprecipitation on T-cell clones showed the presence of a putative non-DR, DQ, DP, TU39+ molecule on phase II clones. However, this molecule was also found on phase I clones. The nature of the TU39-blockable suppressor-inducing determinant present on phase II but not on (most) phase I clones thus remains to be clarified. In addition to suppressor-induction activity, phase II clones also acquired lytic potential as measured in a lectin approximation system. Cytotoxic (CTX) potential was also not influenced by the frequency of antigenic stimulation and could be viewed as a constitutive modulation of clonal function.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1987

HLA-class II antigens on human hematopoietic progenitors.

A panel of alloindifferent monoclonal antibodies (MAB's) was used in complement-dependent lysis to characterize human myeloid, erythroid and multipotential progenitors (CFU-GM, BFU-E, CFU-GEMM) for their expression of MHC class II HLA-DR, -DP, and -DQ products. 7-16 donors were tested in each system. MAB Tü 34, detecting DR products, caused reduction of CFU-GM by a mean of 89%, whereas BFU-E and CFU-GEMM were reduced by 67% and 66% respectively. 35% of CFU-GM, 27% of BFU-E and 32% of CFU-GEMM were lysed by MAB B7/21, recognizing HLA-DP determinants, while Tü 22, binding HLA-DQ antigens, lysed 32% only of CFU-GM and did not lyse the other progenitors. Employing the "broad" MAB Tü 39, which binds at least DR and DP, inhibition of colony formation by CFU-GM was generally greater than that caused by Tü 34 alone or even by combinations of Tü 34, Tü 22, and B7/21. This suggests that there may be a subset of DR-, DP-, DQ- hematopoietic progenitors, which nonetheless bind MAB Tü 39, previously proposed as a candidate for the recognition of novel class II antigens.

Antibodies, Monoclonal↗
PubMed1987

Alloreactive T-lymphocyte clones detecting epitopes uniquely expressed on HLA-D homozygous cells.

Specificity analysis of two unusual alloreactive T-cell clones (TCC) is presented. In repeated in vitro sensitizations of various donors against irradiated HLA-A2, B44, DRw11, DRw52, DQw3, Dw5 homozygous stimulating cells, 202 autonomously proliferating TCC were isolated. Two of these, from different donors, responded against a majority of DRw11 homozygotes, but not against DRw11+ individuals from within or without the family of the original priming cells. Kinetic and stimulator cell titration experiments showed that the reason for this was not to be found in gene-dose effects. One out of 14 non-DRw11+ homozygotes was found that stimulated both TCC: this donor was DRw8+, Dw8+. Stimulation of the TCC was blocked by some anti-DR, and by multi-locus, monoclonal antibodies, but not by those specific for DQ or DP products. Thus, the existence of unique DR-associated stimulating determinants carried only by homozygous cells is demonstrated in man. Physiologically, this might imply that the actual restriction repertoire of HLA-DR homozygotes is not reduced to one half that of heterozygotes as expected.

Antibodies, Monoclonal↗
PubMed1987

Relative cloning efficiencies and long-term propagation capacity for T cell clones of highly purified natural interleukin 2 compared to recombinant interleukin 2 in man.

Highly purified (HP) natural (n) and recombinant (r) interleukin 2 (IL 2) have been compared for their ability to support clonal outgrowth and long-term clonal propagation of alloactivated human T lymphocytes. The frequency of outgrowth of T cell colonies was as high as 1:2 to 1:4 when HPnIL 2 was employed for limiting dilution cloning. Separated CD4+ and CD8+ activated populations produced similar cloning efficiencies. Recloning of established CD4+ lines in HPnIL 2 suggested that a clonable cell frequency of 1:2-1:4 was the maximum possible that could be achieved in this system. In contrast, purified rIL 2 allowed outgrowth of only 1:10-1:20 cells from alloactivated populations. Again, CD4+ and CD8+ fractions generated similar cloning efficiencies. In terms of the fraction of derived clones, which could be propagated to greater than 1 X 10(6) and greater than 1 X 10(8) cells, nIL 2 again proved superior to rIL 2. In either source of IL 2, the proportion of CD4+ clones which could be extensively propagated was greater than in the CD8+ population. Surprisingly, although the addition of PHA to these lectin-free IL 2 preparations reduced the frequency of clonable cells, the proportion of clones which could be extensively propagated was increased. These results suggest that nIL 2, consisting of three differently glycosylated molecular species, may be preferable to rIL 2, which consists only of a single non-glycosylated species, for the cloning and long-term propagation of human T cells. These results may have some bearing on the choice of rIL 2 versus nIL 2 for therapeutic applications.

Cell Division↗