Herbert Schwarz

CD137 Expression in Tumor Vessel Walls High Correlation With Malignant Tumors

CD137 (ILA/4-1BB), a member of the tumor necrosis factor receptor family, and its ligand are expressed on activated T lymphocytes and on antigen-presenting cells, respectively. Via bidirectional signal transduction, this receptor-ligand system regulates the activation, proliferation, and survival of T and B lymphocytes and monocytes. We used immunohistochemical studies on human tissue samples to determine in vivo CD137 expression in nonimmune tissue samples. Strong CD137 expression was found in blood vessel walls, on the endothelial layer, and on the vascular smooth muscle cells. But in 32 healthy tissue samples examined, none contained CD137-positive vessels. Also, in benign tumors (2/14) and in inflammatory tissues (2/9) only a minority had CD137-expressing vessels. However, malignant tumors had a significantly enhanced frequency of CD137-expressing blood vessels (11/34).We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis

CD137 (ILA/4‐1BB) is a member of the tumor necrosis factor receptor family and regulates activation, proliferation and programmed cell death in T lymphocytes. Here we show the existence of a soluble form of CD137 (sCD137) of 16 kDa. sCD137 is released by activated lymphocytes, and in contrast to membrane‐bound CD137, expression of sCD137 seems to be restricted to lymphocytes. sCD137 is generated by alternative splicing and two splice variants were identified. sCD137 is present at low levels in sera of some healthy donors (5/12; mean = 0.18 ng/ml) and is significantly enhanced in sera of patients with rheumatoid arthritis (12/12; mean = 3.58 ng/ml).

Identification of CD137 as a potent monocyte survival factor

CD137 (ILA/4‐1BB), a member of the tumor necrosis factor (TNF) receptor family, promotes adherence and prolongs survival of human peripheral monocytes. It induces a strong expression of macrophage colony‐stimulating factor (M‐CSF), an essential monocyte survival factor. Monocyte survival induced by CD137 is primarily mediated by M‐CSF and to a lesser extent by granulocyte‐macrophage colony‐stimulating factor and IL‐3. Survival and induction of M‐CSF are mediated via reverse signaling through a CD137 ligand expressed constitutively by peripheral monocytes. J. Leukoc. Biol. 65: 829–833; 1999.

CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers

CD137, a member of the TNF receptor family, and its ligand are expressed on T lymphocytes and antigen‐presenting cells (APC), respectively. During interaction with APC, T lymphocytes receive a potent, costimulatory signal through CD137. Reverse signaling has been demonstrated for the CD137 ligand, which causes activation in monocytes. Here we show that B lymphocytes also receive costimulatory signals through the CD137 ligand. Immobilized CD137 augmented proliferation of preactivated B lymphocytes up to fivefold and immunoglobulin synthesis, up to threefold. CD137 had no effect on resting cells. Further, we show that CD137 is expressed in vivo by follicular dendritic cells (FDC) in germinal centers. Germinal centers form during humoral immune responses and are essential for B lymphocyte affinity maturation. These data imply that, similar to the CD40 receptor/ligand system, which mediates T lymphocyte help to B lymphocytes after the first antigen encounter, the CD137 receptor/ligand system may mediate costimulation of B lymphocytes by FDC during affinity maturation.

CD137 Expression in Tumor Vessel Walls

CD137 (ILA/4-1BB), a member of the tumor necrosis factor receptor family, and its ligand are expressed on activated T lymphocytes and on antigen-presenting cells, respectively. Via bidirectional signal transduction, this receptor-ligand system regulates the activation, proliferation, and survival of T and B lymphocytes and monocytes. We used immunohistochemical studies on human tissue samples to determine in vivo CD137 expression in nonimmune tissue samples. Strong CD137 expression was found in blood vessel walls, on the endothelial layer, and on the vascular smooth muscle cells. But in 32 healthy tissue samples examined, none contained CD137-positive vessels. Also, in benign tumors (2/14) and in inflammatory tissues (2/9) only a minority had CD137-expressing vessels. However, malignant tumors had a significantly enhanced frequency of CD137-expressing blood vessels (11/34).

CD137‐induced apoptosis is independent of CD95

CD95 (APO‐1/Fas) and CD137 (ILA/4‐1BB) are members of the tumour necrosis factor receptor family, and both are involved in induction of apoptosis in lymphocytes. Contrary to the case of CD95, apoptosis by CD137 is caused by cross‐linking of the respective ligand rather than the receptor. Nothing is known so far about the mechanism of CD137‐induced cell death. Here, we show that immobilized CD137 protein induces expression of CD95 in resting primary T and B lymphocytes. However, induction of apoptosis by CD137 is independent of CD95, because: (1) antagonistic anti‐CD95 antibody fragments do not block CD137‐induced apoptosis; and (2) CD137, but not anti‐CD95, can induce apoptosis in resting lymphocytes.

Stage-specific antigens reacting with monoclonal antibodies against contact site A, a cell-surface glycoprotein of Dictyostelium discoideum

Monoclonal antibodies against a glycoprotein presumably involved in adhesion of aggregating Dictyostelium discoideum cells have been used for labeling of the antigen at the cell surface. The antigen is distributed over the whole surface of the cells, apparently in form of small clusters. The antigen appears concomitantly with the acquisition of EDTA-stable adhesiveness typical of aggregation competent cells. In contrast, discoidin I, a lectin whose accumulation during development parallels EDTA-stable adhesiveness in another strain (NC-4), is present in nearly the same amounts of growth phase and aggregating cells of AX2-214, the strain used by use. Thus, no correlation exists in this strain between the expression of discoidin I and the development of cell adhesiveness. The 80 kilodalton glycoprotein typical of aggregation competent cells has been purified by affinity chromatography on a monoclonal antibody column. The purified antigen absorbs adhesion-blocking Fab from rabbits. Another antigen strongly reacting with the same monoclonal antibodies has an apparent molecular weight of 106 000 and is not detectable before slugs are formed.

Expression of CD137 and its ligand in human neurons, astrocytes, and microglia: Modulation by FGF‐2

CD137 (ILA, 4‐1BB), a member of the tumor necrosis factor receptor family, and its ligand CD137‐L were assayed by RT‐PCR and immunocytochemistry in cultured human brain cells. Results demonstrated that both neurons and astrocytes expressed specific RNA for CD137 and its protein, which was found both on the plasma membrane and in the cytoplasm. Surprisingly, microglia, which also expressed CD137 mRNA, showed negative immunostaining. CD137‐L‐specific RNA was detected only in astrocytes and neurons. When brain cells were treated with fibroblast growth factor‐2 (FGF‐2), upregulation of CD137 but not of its ligand was observed in neurons and astrocytes. Protein localization was also affected. In microglia, an inhibition of RNA expression was induced by treatment, whereas CD137‐L remained negative. Our data are the first demonstration that human brain cells express a protein found thus far in activated immunocompetent cells and epithelia. Moreover, they suggest not only that CD137 and CD137‐L might play a role in interaction among human brain cells, but also that FGF‐2 might have an immunoregulatory function in brain, modulating interaction of the central nervous system with peripheral immunocompetent cells.

Inhibition of cytokines expression in human microglia infected by virulent and non-virulent mycobacteria

The pathogenesis of tuberculosis (TBC) meningitis is still unknown. As shown by previous studies, human microglia can be the target of mycobacteria, but no data are available about their cellular response to infection. Consequently, we studied the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-10 in human microglia pure cultures infected with the two variants of Mycobacterium avium (domed-opaque (SmD) and transparent (SmT)) and with Mycobacterium tuberculosis. Results showed that microglia was productively infected by mycobacteria which could grow inside the cells. Mycobacteria internalization was more rapid for M. avium, but M. tuberculosis infection turned out to be more efficient due to the incorporation of densely packed bacteria. TNF-alpha expression was not affected by M. avium, whereas an increase followed by a decrease was observed in M. tuberculosis. Both IL-1 and IL-10 cytokine expression was rapidly inhibited by infection with the more virulent bacteria, whereas the non-pathogenic one had almost no effect. Also, the expression of the co-stimulatory molecule CD137, a member of tumor necrosis factor receptor family, was affected by infection with virulent mycobacteria. Our results show that microglia response to mycobacterial infection is modulated in correlation with virulence, mainly toward inhibition of inflammatory response. This observation might be one of the mechanisms by which non-pathogenic mycobacteria are quickly eliminated, explaining one of the bases of virulence.

Cis-9,10-octadecenoamide, an endogenous sleep-inducing CNS compound, inhibits lymphocyte proliferation

This study examined the immunoregulatory effects of cis-9,10-octadecenoamide (CODA), a recently identified endogenous sleep-inducing brain lipid. CODA displays structural and functional similarities to anandamide, the endogenous ligand for the cannabinoid receptors. CODA proved to be immunosuppressive. It inhibited proliferation of anti-CD3- and ConA-activated primary lymphocytes and proliferation of T- and B-cell lines. Complete inhibition occurred at concentrations of 100 microM. This effect was stereospecific, since the trans-stereo isomer of CODA did not inhibit proliferation at identical concentrations. A further control compound, octadecanamide, identical to cis-9,10-octadecenoamide, besides lacking the 9,10 carbon double bond, also did not affect proliferation. The antiproliferative effects of CODA occurred rapidly, since 24-h exposure to CODA was sufficient for complete inhibition of proliferation. CODA and anandamide worked synergistically in inhibiting lymphocyte proliferation. No significant effects of CODA on monocyte functions, as assessed by LPS-induced TNF alpha secretion, could be detected.