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D Kabelitz

Publications and source records attributed to D Kabelitz.

At least 37 records · Page 2Linked to original sources
PubMed1992

Life and death of a superantigen-reactive human CD4+ T cell clone: staphylococcal enterotoxins induce death by apoptosis but simultaneously trigger a proliferative response in the presence of HLA-DR+ antigen-presenting cells.

We report that a human CD4+ T cell clone with specificity for staphylococcal enterotoxin (SE) superantigens A, D, and E can respond to SEs in two seemingly opposite ways. In the absence of antigen presenting cells (APC), SEA, D, and E (but not SEB or C1) strongly inhibited in a dose-dependent manner the responsiveness of clone D894/25 to exogenous IL-2. Growth inhibition was due to SE-induced programmed cell death (apoptosis) as shown by propidium iodide staining and the appearance of the characteristic ladder pattern of DNA fragmentation. Apoptotic cell death was accompanied by significant cell lysis after 4 and 8 h as measured in a 51Cr release assay. In contrast (but as expected), a proliferative response of clone D894/25 was triggered by SEA, D, and E in the absence of exogenous IL-2 but presence of HLA class II-positive lymphoblastoid cell line (LCL) as APC. Moreover, the addition of LCL feeder cells partially prevented the suppression of IL-2 responsiveness by SEs. Surprisingly, however, the latter two culture conditions (i.e. presence of LCL feeder cells with or without exogenous IL-2) were associated with similar levels of induced cell death as in the absence of LCL. At the clonal level, these data demonstrate that SE superantigens induce programmed cell death in a fraction (40-50%) of responsive mature T cells, irrespective of the presence or absence of MHC class II-positive APC. We conclude that the proliferative response of clone D894/25 which is triggered by SEs in the presence of APC and absence of IL-2 must originate from the fraction (50-60%) of clone T cells surviving SE-induced cell death.

Antigen-Presenting Cells↗
PubMed1992

Preferential activation of peripheral blood V gamma 9+ gamma/delta T cells by group A, B and C but not group D or F streptococci.

Previous studies have established that inactivated mycobacteria are potent and selective activators of V gamma 9+/V delta 2+ human gamma/delta T cells. Here we have analysed the proliferative response of human gamma/delta T cells to five serologically distinct groups of streptococci. While heat-inactivated streptococci of all five serogroups tested (A, B, C, D and F) induced a strong proliferative response in peripheral blood mononuclear cells (PBMC), only groups A, B and C elicited a selective activation of V gamma 9+ gamma/delta T cells in 10 (serogroup B) or 11 (serogroups A and C) of 11 tested healthy individuals. In striking contrast, groups D and F streptococci failed to activate gamma/delta T cells in nine of 11 donors and induced only a weak gamma/delta T cell response in two additional individuals. Depletion of V gamma 9+ T cells before culture completely eliminated all gamma/delta T cell responses to streptococci. These data indicate that groups A, B and C (but not D or F) streptococci can be included in the growing list of selective ligands for V gamma 9+/V delta 2+ human gamma/delta T cells.

Cells, Cultured↗
PubMed1992

Frequency analysis of allergen-reactive T-lymphocytes in individuals allergic against the house-dust mite Dermatophagoides pteronyssinus.

We have investigated the frequencies of Dermatophagoides pteronyssinus (Dpt)-reactive circulating T cells in individuals allergic to this house dust mite and in asymptomatic controls. In allergic patients the median for frequencies of Dpt-reactive T cells (80/10,000 T cells) was significantly higher (p = 0.0001) than that in the controls (19/10,000 T cells). Frequencies of spontaneously proliferating T cells were also determined. Here too, marked differences (p = 0.0001) were observed between the allergics (median = 32/10,000 T cells) and the non-allergics (median = 7.5/10,000 T cells). The allergen-reactive T cells tended to occur at a higher frequency with increasing serum level of Dpt-specific IgE. Thus the median value for Dpt-reactive T cells in patients showing RAST class greater than or equal to 4 (176.5/10,000 T cells) was higher than that shown by patients with RAST class 3 (62/10,000 T cells). Frequency estimations of allergen-reactive T cells before, during and after the completion of hyposensitization therapy might help to clarify their possible role in the allergic symptoms.

Allergens↗
PubMed1992

The decidua of early human pregnancy: immunohistochemistry and function of immunocompetent cells.

Like the endometrial stroma, the decidua contains lymphoreticular cells, and these are probably involved in immunological interactions between the conceptus and the mother. Lymphoreticular cells in decidual tissue obtained from 12 patients undergoing therapeutic abortion of an intact pregnancy at 6-10 weeks' gestation were investigated in this study. Immunophenotyping with a broad panel of monoclonal antibodies revealed various subpopulations of lymphoreticular cells. Macrophages (Ki-M6+, Ki-M7+, Ki-M8+, KP1+, MAC 387+ and Ki-M1P+) represented the largest fraction of intradecidual lymphoreticular cells. CD3+ and CD8+ lymphocytes were found in moderate numbers and CD4+ cells in small numbers. The majority of the intradecidual lymphoid cells exhibited an unusual phenotype [CD7+, CD2+, CD56+, triple negative (CD3-, CD4-, CD8)]. The distribution of these unusual lymphocytes mirrored that of the so-called endometrial stromal granulocytes. A few of these stromal granulocytes reacted with the macrophage-associated antibody KP1, but not with Ki-M1P, another macrophage marker. This was confirmed by immuno-electron microscopy. The finding that intradecidual CD3+ lymphocytes express neither the alpha/beta nor the gamma/delta heterodimer of the T cell antigen receptor was unexpected. However, these cells did express the alpha/beta heterodimer after in vitro culture with PHA-P and recombinant exogenous interleukin-2. No stimulated T lymphocytes expressing activation antigens could be detected. B lymphocytes, T and B immune accessory cells and CD15+ granulocytes were found only in small numbers or were absent. Amongst cells expressing NK cell markers, CD57+ and CD16+ cells were found in small to moderate numbers, while CD56+ cells were detected in large numbers.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Function and specificity of human gamma/delta-positive T cells.

gamma/delta+ T-cells are a recently identified subpopulation of T-lymphocytes expressing an "alternative" T-cell receptor (TCR) molecule consisting of disulfate-linked or nonlinked gamma and delta chains. Despite a limited number of V gamma and V delta genes in the germ line, there is a large and diverse gamma delta TCR repertoire due to extensive N region variability. Recently developed monoclonal antibodies against V gamma and V delta gene products are useful reagents for the identification and isolation of gamma/delta+ T-cell subpopulations. The physiological significance of gamma/delta+ T-cells is still unknown. However, accumulating evidence indicates that human gamma/delta+ T-cells frequently recognize bacterial ligands as well as certain tumor cells. Interestingly, reactivity towards microbial antigens is usually restricted to a subpopulation of gamma/delta+ T-cells expressing a V gamma 9/V delta 2 TCR. However, different bacteria-reactive V gamma 9+/V delta 2+ gamma/delta+ T-cells display extensive N region variability, suggesting the involvement of a gamma/delta-specific superantigen in these responses. Little is known about the role of gamma/delta+ T-cells under pathological conditions. Rare cases of gamma/delta+ T-cell leukemias and lymphomas have been described. In addition, discrete changes in the distribution of gamma/delta+ T-cell subpopulations have been observed during HIV infection. Current thinking favors the interpretation that gamma/delta+ T-cells play a role in the immune reaction during infection and in the regulation of physiological or pathophysiological autoimmune responses.

Epitopes↗
PubMed1992

B-cell maturation in chronic lymphocytic leukaemia. IV. T-cell-dependent activation of leukaemic B cells by staphylococcal enterotoxin 'superantigens'.

Staphylococcal enterotoxins (SE) are potent T-lymphocyte activators that stimulate T cells by directly cross-linking HLA-DR molecules on antigen-presenting cells with the V beta gene products of the T-cell receptor. The different SE activate all T cells expressing a given V beta, and, therefore, have been termed 'superantigens'. Here we show that SE are potent activators of leukaemic B cells from patients with chronic lymphocytic leukaemia (CLL). Purified B cells from seven of eight CLL patients with high WBC counts (greater than 80,000/microliters) responded to one or several of the tested SE (SEA, SEB, SEC1, SED, SEE) by proliferation ([3H]TdR incorporation) and/or Ig secretion. In several instances, the response of leukaemic B cells to SE was much stronger than was the response to other known B-cell activators including EBV, pokeweed mitogen (PWM), phorbolester (TPA), and Staphylococcus aureus Cowan I (SAC). The activation of leukaemic B cells by SE was strictly dependent on the addition of irradiated T cells isolated from healthy donors. FACS analysis of cultured cells ensured that the proliferating cells were indeed B cells. Taken together, these results demonstrate that SE are strong T-cell-dependent B-cell activators that, in some cases, can stimulate maturation of leukaemic B cells which are refractory to other activation signals.

Antigens, Bacterial↗
PubMed1991

Perspectives in transplantation immunology 1991.

The clinical success of organ transplantation depends to a large degree on the immunological acceptance of the grafted organ. This paper summarizes from an immunological point of view the recent progress that has been made to improve graft acceptance, and discusses some future aspects in the field. Over the last few years, major emphasis has been put on the development of new immunosuppressive drugs, including FK 506, rapamycin, and Deoxyspergualin. Together with monoclonal antibodies against defined T-cell surface antigens, there are now new and effective means available to prevent or treat rejection episodes. Progress has also been made in the field of HLA typing, where the introduction of molecular biology-based methods significantly increased the accuracy of HLA class II typing. The ultimate goal of transplantation immunology is the induction of (donor-) specific tolerance. While some protocols are effective in inducing peripheral tolerance in experimental animals, these regimens are at present not yet applicable in the clinical situation. To overcome the shortage of donor organs, alternative strategies are currently being considered. Among these, xenotransplantation may eventually prove successful, despite the massive immunological problems such as, e.g., the presence of preformed xenoreactive antibodies.

Animals↗
PubMed1991

The primary response of human gamma/delta + T cells to Mycobacterium tuberculosis is restricted to V gamma 9-bearing cells.

We have previously reported that peripheral blood gamma/delta + T cells proliferate in high frequency (1 in 2-20) in response to heat-killed Mycobacterium tuberculosis (M.tb.). In the present study, the T cell receptor phenotype of mycobacteria-responsive human gamma/delta + T cells was analyzed in primary cultures with a set of monoclonal antibodies (mAbs) directed against V gamma 9, V delta 1, and V delta 2. When unseparated T cells were stimulated with M.tb., all proliferating gamma/delta + T cells expressed V gamma 9 (and V delta 2) after culture. Selective depletion of V gamma 9-bearing cells before culture completely abolished the proliferative response of all gamma/delta + cells (but did not inhibit reactivity of alpha/beta + T cells). In addition, when CD4- CD8- thymocytes were stimulated with M.tb., there was again selective outgrowth of V gamma 9+ cells. In this case, the starting responder population contained few (0.5-1.8%) V gamma 9+ and many (11.5-31.5%) V delta 1+ cells that did not coexpress V gamma 9. These V delta 1+ cells were not activated by M.tb. but could be readily stimulated by anti-V delta 1 mAb A13. Finally, a V gamma 9-specific mAb selectively suppressed the proliferative response of gamma/delta + T cells to M.tb. Taken together, our results demonstrate that, within gamma/delta + T cells, reactivity towards M.tb. is an exclusive property of V gamma 9+/V delta (2+)-bearing cells.

Antibodies, Monoclonal↗
PubMed1991

Selective activation of gamma/delta + T cell clones by single anti-CD2 antibodies.

The CD2 antigen is the target for an "alternative" T cell activation pathway. Numerous studies have demonstrated that pairs of monoclonal antibodies (mAbs) directed toward two different epitopes are required for activation of T cell receptor (TCR)-alpha/beta + T cells via CD2. We have now explored the activation of human TCR-gamma/delta + T cell clones by a panel of anti-CD2 mAbs directed against the sheep erythrocyte-binding (T11.1) epitope of CD2. Seven of seven gamma/delta + clones expressing different molecular forms of the TCR-gamma/delta responded to stimulation by a single anti-CD2 mAb (OKT11, 9E8, BW0110, M-T910) with IL-2 secretion and/or proliferation. Immobilization of anti-CD2 mAbs in microculture plates was essential for activation of gamma/delta + clones, which occurred in the absence of feeder cells. In addition to interleukin 2 (IL-2) production and proliferation, anti-CD2 mAbs also triggered cytotoxic effector activity in gamma/delta + clones as measured against FcR+ P815 target cells. In contrast to gamma/delta + clones (but in line with established data), none of five CD4+ or CD8+ TCR-alpha/beta + clones were activated by any of the tested individual anti-CD2 mAbs. Taken together, our results reveal a striking difference between cloned gamma/delta + and alpha/beta + T cells in that gamma/delta + T cells are selectively activated by a single anti-CD2 (T11.1) mAb, without need for the simultaneous signal of a second anti-CD2 mAb directed against another (T11.2 or T11.3) CD2 epitope.

Animals↗
PubMed1991

T cell receptor/CD3-signaling induces death by apoptosis in human T cell receptor gamma delta + T cells.

mAb directed against the TCR/CD3 complex activate resting T cells. However, TCR/CD3 signaling induces death by apoptosis in immature (CD4+CD8+) murine thymocytes and certain transformed leukemic T cell lines. Here we show that anti-TCR and anti-CD3 mAb induce growth arrest of cloned TCR-gamma delta + T cells in the presence of IL-2. In the absence of exogenous IL-2, however, the very same anti-TCR/CD3 mAb stimulated gamma delta (+)-clones to proliferation and IL-2 production. In the presence of exogenous IL-2, anti-TCR/CD3 mAb induced the degradation of DNA into oligosomal bands of approximately 200 bp length in cloned gamma delta + T cells. This pattern of DNA fragmentation is characteristic for the programmed cell death termed apoptosis. These results demonstrate that TCR/CD3 signaling can induce cell death in cloned gamma delta + T cells. In addition, this report is the first to show that apoptosis triggered by TCR/CD3 signaling is not restricted to CD4+CD8+ immature thymocytes and transformed leukemic T cell lines but can be also observed with IL-2-dependent normal (i.e., TCR-gamma delta +) T cells.

Antibodies, Monoclonal↗
PubMed1991

Stimulation of CD2-negative T cells by staphylococcal enterotoxin superantigens.

A minor fraction of CD3+ T cells lacks expression of the CD2 antigen, which is the target for an "alternative" T cell activation pathway. CD2-CD3+ T cells can be stimulated by anti-CD3 or anti-T cell receptor (TCR) antibodies, indicating that the CD3/TCR signal transduction pathway functions in the absence of cell surface CD2. In the present study we have analyzed whether CD2-CD3+ T cells also respond to antigen stimulation. We show here that cloned CD2-negative T cells expressing the alpha/beta TCR are activated by one or several staphylococcal enterotoxin "superantigens". Activation of CD2-CD3+ T cell clones by staphylococcal enterotoxins resulted in IL-2 production and/or proliferative activity, and was dependent on the presence of HLA class II-bearing feeder cells. These data demonstrate that T cells can recognize (and respond to) antigen in the absence of a functional CD2 molecule.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

[Cytokine production by gynecologic cancers].

Aggressive polychemotherapy and ultraradical surgery had had only small benefits for patients with gynaecological cancer in recent years. That is why we measured cytokines in these patients to evaluate a possible future immune therapy. To investigate the influence of gynaecological cancer on in vitro and in vivo cytokine production of peripheral mononuclear cells (PBMC) from 27 patients with mamma carcinoma and 29 patients with cervical cancer, we evaluated the production of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). We compared the immune function of these patients versus 20 patients who had had routine hysterectomies performed for non-malignant reasons and 20 healthy female controls. Blood for cytokine production was collected prior to surgery, for IFN-alpha-production two weeks after surgery and for all cytokines three months after surgery. Measurement of TNF-alpha-production did not differ significantly in all investigated groups. IFN-gamma-production was reduced by 50% in patients with mamma carcinoma in three months - possibly caused by chemotherapy and radiation. The amount of IFN-alpha production in cancer patients was dramatically reduced before primary therapy started. The low levels of IFN-alpha persisted for three months compared to the IFN-alpha production in non-cancer patients and healthy controls. The follow-up of patients with breast cancer undergoing chemotherapy showed a suppressive effect on immunological function in IFN-alpha. Our results demonstrate, that patients with breast cancer and cervical cancer showed a significantly reduced capacity to product IFN-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Activation and activation-driven death of human gamma/delta T cells.

We have concentrated on three functional aspects of human gamma/delta+ T cells. (1) Peripheral blood gamma/delta+ T cells proliferate at a high frequency in response to heat-killed mycobacteria (M.tb.). We present evidence that the primary response of human gamma/delta+ T cells is restricted to those cells bearing a V gamma 9/V delta 2 receptor. (2) T cells expressing the alpha/beta TCR can be activated through the CD2 antigen via an "alternative" pathway. Activation requires the combined signaling of 2 mAb directed against two distinct epitopes of CD2. In striking contrast, cloned gamma/delta+ T cells are activated by a single immobilized anti-CD2 mAb directed against the sheep E-binding epitope of CD2. Stimulation of cloned gamma/delta+ T cells by a single anti-CD2 mAb results in IL-2 production, proliferation, and triggering of cytolytic effector function. (3) Cloned gamma/delta+ T cells are susceptible to programmed cell death (apoptosis) when stimulated simultaneously by anti-CD3/TCR mAb plus exogenous IL-2. The very same clones are activated, however, by the same stimuli in the absence of exogenous IL-2 (but in the presence of LCL feeder cells). This provides the basis for a model where extensive gamma/delta+ T cell proliferation is negatively regulated by antigen plus IL-2.

Antibodies, Monoclonal↗