Biomedical subjects

D Olive

Publications and source records attributed to D Olive.

At least 19 recordsLinked to original sources

PubMed1999

Full peptide synthesis, purification, and characterization of six Tat variants. Differences observed between HIV-1 isolates from Africa and other continents.

AIDS in Africa is characterized by the equal distribution of mortality between the two genders because of highly virulent human immunodeficiency virus type 1 (HIV-1) strains. The viral protein Tat trans-activates viral gene expression and is essential for HIV-1 replication. We chemically synthesized six different Tat proteins, with sizes ranging from 86 to 101 residues, from HIV-1 isolates located in different parts of the world including highly virulent African strains. Protein purification, mass spectroscopy, and amino acid analysis showed that the synthesis was successful in each case but with different yields. We show that all have the ability to bind the HIV long terminal repeat (LTR) RNA trans-activation response element (TAR) region, involved in Tat-mediated trans-activation, but structural heterogeneities are revealed by circular dichroism. These Tat synthetic proteins cross membranes but differ in their ability to trans-activate an HIV LTR-reporter gene in stably transfected HeLa cells. Two Tat proteins from virulent African HIV-1 strains were much more active than those from Europe and the United States. The interferon-induced kinase (PKR), involved in cell antiviral defense, phosphorylates only Tat variants corresponding to less or nonvirulent HIV-1 isolates. Our results indicate that the high virulence of some African HIV-1 strains could be related to Tat activity.

Amino Acid Sequence↗

PubMed1999

Human immunodeficiency virus type 1 Nef protein sensitizes CD4(+) T lymphoid cells to apoptosis via functional upregulation of the CD95/CD95 ligand pathway.

Many viruses have evolved genes encoding proteins that regulate cell death by apoptosis. The human immunodeficiency virus type 1 (HIV-1) Nef protein alters T-cell development and signaling and is required for optimal viral replication and pathogenicity in vivo. To analyze the interference of Nef with cell survival, we used both regulated and constitutively expressed nef alleles in stably transfected T-cell lines. Nef-expressing cells were sensitized to cell death by apoptosis, which was specifically exacerbated by an anti-CD95 IgM monoclonal antibody (MoAb). Flow cytometric analysis showed that the surface expression of both CD95 and CD95 ligand (CD95L) was upregulated by endogenous Nef expression. Nef-mediated apoptosis was almost completely suppressed by the addition in culture of an anti-CD95 Fab' IgG MoAb, which specifically blocks CD95/CD95L interactions. Lastly, mutation of a proline motif in the core region of the nef gene, which disrupts its ability to interact with cellular kinases and reduces HIV-1 replication in vitro, completely abrogated the Nef-mediated induction of apoptosis as well as its ability to upregulate surface CD95 and CD95L. These findings may provide molecular insight into the role of endogenous Nef in the T-cell depletion observed in vivo, particularly HIV-specific cytotoxic CD8(+) T cells.

Apoptosis↗

PubMed1999

The role of Tec protein-tyrosine kinase in T cell signaling.

The Tec protein-tyrosine kinase family includes Btk, Itk/Tsk/Emt, Tec, Rlk/Txk, and Bmx which are involved in signals mediated by various cytokines or antigen receptors. Itk is expressed primarily in T cells and activated by TCR/CD3, CD28, and CD2. However, the defect in T cell signaling in itk-deficient mice is very modest. Thus, we looked for other Tec family kinases that could be expressed in lymphoid cells and involved in T cell signal transduction. Here, we demonstrate that Tec, expressed in T cells, is activated following TCR/CD3 or CD28 ligation and interacts with CD28 receptor in an activation-dependent manner. This interaction involves the Tec SH3 domain and the proline-rich motifs in CD28. We also show that Tec can phosphorylate p62(dok), one CD28-specific substrate, whereas Itk cannot. Overexpression of Tec but not Itk can enhance the interleukin-2 promoter activity mediated by TCR/CD3 or CD28 stimulation and introduction of a kinase-dead Tec but not Itk can suppress interleukin-2 expression, indicating that Tec is directly involved in T cell activation. Altogether, these data demonstrate that Tec kinase is an integral component of T cell signaling and that the two Tec family kinases, Tec and Itk, have distinct roles in T cell activation.

Amino Acid Sequence↗

PubMed1999

Tec kinase is involved in transcriptional regulation of IL-2 and IL-4 in the CD28 pathway.

The Tec protein tyrosine kinase (PTK) family includes Btk, Itk/Tsk/Emt, Tec, Rlk/Txk and Bmx, which are involved in signals mediated by various surface receptors. We have previously found (W.-C. Yang et al., J. Biol. Chem. 1999. 274: 607) that Tec is involved in T cell signaling in a way distinct from Itk. However, little is known about the role of Tec in regulation of cytokine expression in the CD28 pathway. Here, we show in heterologous COS-7 cells that co-expression of Src family kinases such as Lck increases Tec activation or CD28-mediated Tec activation, whereas co-expression of kinase-dead Lck blocks Tec activation or CD28-mediated Tec activation. These data suggest that CD28 activates Tec via Src family PTK. As is the case for the IL-2 promoter, transcription of the IL-4 promoter is enhanced by overexpression of wild-type Tec but inhibited by overexpression of a kinase-dead version of Tec following CD28 activation. These results imply that Tec can modulate transcription of Th1 and Th2 cytokines in a kinase-dependent manner. Consistent with the hypothesis postulated above that Lck can regulate Tec activation, overexpression of kinase-dead Lck can block Tec-induced cytokine expression following CD28 ligation.

Amino Acid Sequence↗

PubMed1999

[Mechanisms of tumor escape from immunologic response].

INTRODUCTION: The rationale for immune control of cancer is now better defined via the immunovirology of transforming viruses, definition of human tumor antigens recognized by T-lymphocytes, and cellular and humoral components of the anticancer response. Nonetheless tumors can escape from immune surveillance. To better define immunomodulation strategies, we describe some of the various strategies developed by transformed cells to evade the immune response. CURRENT KNOWLEDGE AND KEY POINTS: Both the lack of specific tumor antigen and down-regulation of major histocompatibility complex (MHC) molecule expression hamper recognition of neoplastic cells by T-lymphocytes. In presence of defective expression of ligands for the T-cell co-stimulatory receptors, tumor recognition may lead to the development of tolerance instead of specific cytotoxic activity. Tumor cell counter-attack against effector T-cells has also been described, using either inhibitory cytokines (IL-10), apoptosis induction (via Fas signalling), functional inactivation (disruption of normal CD40/CD40 ligand interactions), or induction of anergy. FUTURE PROSPECTS AND PROJECTS: Despite the many different mechanisms of tumor escape, the immune system has developed efficient counter-attacks. For instance, natural killer cells may detect and destroy tumor cells that lack class 1 MHC molecules and thus escape from specific T-lymphocyte cytolysis. Moreover, immunogenicity can be restored, at least in vitro, by different means such as tumor cell stimulation by cytokines or CD40, suggesting that therapeutic strategies will soon be developed in order to stimulate an efficient antitumoral immune response.

Antibody Formation↗

PubMed1999

HOX gene expression is altered in the endometrium of women with endometriosis.

HOXA10 and HOXA11 are homeobox genes that function as transcription factors essential to embryonic development. We have recently described a role for each of these two genes in regulating endometrial development in the adult during the course of a menstrual cycle. Both Hoxa10 and Hoxa11 are essential for implantation in the mouse and appear to play a similar role in women. To investigate the role of HOX genes in the endometrium of women with endometriosis, quantitative Northern blot analysis was performed on the endometrium of 40 normal cycling controls and 40 patients with documented endometriosis. Patients with endometriosis failed to show the expected mid-luteal rise in HOX gene expression as demonstrated in the controls. Aberrant HOX gene expression suggests that altered development of the endometrium at the molecular level may contribute to the aetiology of infertility in patients with endometriosis.

Adult↗

PubMed1999

Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients.

We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines.

Adolescent↗

PubMed1999

Interaction of Brucella abortus lipopolysaccharide with major histocompatibility complex class II molecules in B lymphocytes.

Lipopolysaccharide (LPS), a major amphiphilic molecule located at the outer membrane of gram-negative bacteria, is a potent antigen known to induce specific humoral immune responses in infected mammals. LPS has been described as a polyclonal activator of B lymphocytes, triggering the secretion of antibodies directed against distinct sugar epitopes of the LPS chain. But, how LPS is handled by B cells remains to be fully understood. This task appears to be essential for a better knowledge of the anti-LPS humoral immune response. In this study, we examine the internalization of LPS and its interaction with antigen-presenting major histocompatibility complex (MHC) class II molecules in murine and human B-cell lines. By use of immunofluorescence, we observe that structurally different LPSs from Brucella and Shigella strains accumulate in an intracellular compartment enriched in MHC class II molecules. By use of immunoprecipitation, we illustrate that only Brucella abortus LPS associates with MHC class II molecules in a haplotype-independent manner. Taken together, these results raise the possibility that B. abortus LPS may play a role in T-cell activation.

Animals↗

PubMed1999

Simian immunodeficiency virus and human immunodeficiency virus type 1 nef proteins show distinct patterns and mechanisms of Src kinase activation.

The nef gene from human and simian immunodeficiency viruses (HIV and SIV) regulates cell function and viral replication, possibly through binding of the nef product to cellular proteins, including Src family tyrosine kinases. We show here that the Nef protein encoded by SIVmac239 interacts with and also activates the human Src kinases Lck and Hck. This is in direct contrast to the inhibitory effect of HIV type 1 (HIV-1) Nef on Lck catalytic activity. Unexpectedly, however, the interaction of SIV Nef with human Lck or Hck is not mediated via its consensus proline motif, which is known to mediate HIV-1 Nef binding to Src homology 3 (SH3) domains, and various experimental analyses failed to show significant interaction of SIV Nef with the SH3 domain of either kinase. Instead, SIV Nef can bind Lck and Hck SH2 domains, and its N-terminal 50 amino acid residues are sufficient for Src kinase binding and activation. Our results provide evidence for multiple mechanisms by which Nef binds to and regulates Src kinases.

Amino Acid Sequence↗

PubMed1999

Tumor escape from immune surveillance.

The bases for an efficient anti-tumor immune response begin to be better defined. Nonetheless, neoplastic cells develop various strategies to escape immune surveillance, which are discussed here in order to better design the therapeutic possibilities of immune manipulation. The absence of specific tumor antigen as well as the weak expression of major histocompatibility complex (MHC) molecules hinder the recognition of the neoplastic cells by T lymphocytes. The defect of expression by the tumor of the ligands for the T cell activation costimulatory molecules is particularly harmful for the immune response since it induces tolerance. Finally, tumor cells can inactivate effector T lymphocytes through the secretion of inhibitory cytokines, induction of apoptosis or functional inactivation. The multiplicity of the means to oppose an effective anti-tumor response challenges the adaptative mechanisms of the immune system. For example, the natural killer cells target tumor cells not expressing MHC class I molecules. Numerous possibilities of tumor immunogenicity restoration have been demonstrated at least in vitro, such as stimulation of the cancerous cells by CD40 or cytokine treatment, which could lead to several promising therapeutical approaches.

Humans↗

PubMed1999

Differential modulation of immune recognition molecules by interleukin-7 in human acute leukaemias.

Clinical animal models and in vitro data afford evidence for anti-leukaemia immunity. Many reports have underlined the interest of interleukin-7 (IL-7) use in cancer and its pivotal role in immune recognition. This cytokine, initially identified as a B cell growth factor, enhances the anti-tumour properties of immune effector cells via T lymphocyte activation, increased specific cytotoxicity and cytokine secretion. Nonetheless, few data are available regarding the effect of IL-7 on the expression at the leukaemia cell surface of molecules involved in the immune response, which defective expression could induce tolerance or anergy. This prompted us to study the effects of IL-7 on 20 cases of acute myeloid leukaemia (AML) and 9 cases of lymphoid leukaemia (ALL), in comparison with gamma-interferon, a potent inducer of immune regulation molecule expression. In AML and ALL, IL-7 increased MHC class I molecule expression, while class II molecules were weakly modified. The expression of the tumour necrosis factor family members CD40 and Fas/CD95, together with the adhesion molecules ICAM-1/CD54 and CD58/LFA-3, was also increased in both types of leukaemia. The IL-7 was an efficient inducer of B7-2/CD86 expression in AML and ALL, while increased expression of B7-1/CD80 was only observed in AML. In the corresponding, co-cultured T lymphocyte population, IL-7 more particularly increased B7-1/CD80 and CD58/LFA-3 expression. Finally, pre-incubation of leukaemic cells with IL-7 increased the proliferation of responding, normal allogenic T lymphocytes and their secretion of gamma-IFN and IL-2 in mixed the lymphocyte-tumour reaction. We concluded that IL-7 is efficient at increasing the membrane expression of molecules which are central for the development of the immune response, and at improving allogenic immune recognition. The clinical implications of such data require further in vivo investigation.

Antigens, CD↗

PubMed1998

Distinct regulation of T-cell death by CD28 depending on both its aggregation and T-cell receptor triggering: a role for Fas-FasL.

CD28 is a major coreceptor that regulates cell proliferation, anergy, and viability of T cells. The negative selection by T-cell receptor (TCR)-induced cell death of immature thymocytes as well as of activated human antigen-specific T-cell clone, requires a costimulatory signal that can be provided by CD28. Conversely, CD28-mediated signals increase expression of Bcl-XL, a survival gene, and promote survival of naive T cells cultured in the absence of antigen or costimulation. Because CD28 appears to both protect from, or induce T-cell death, one important question is to define the activation and cellular parameters that dictate the differential role of CD28 in T-cell apoptosis. Here, we compared different CD28 ligands for their ability to regulate TCR-induced cell death of a murine T-cell hybridoma. In these cells, TCR triggering induced expression of Fas and FasL, and cell death was prevented by anti-Fas blocking monoclonal antibody (MoAb). When provided as a costimulus, both CD28 MoAb and the B7.1 and B7.2 counter receptors downregulated, yet did not completely abolish T-cell receptor-induced apoptosis. This CD28 cosignal resulted in both upregulation of Bcl-XL and prevention of FasL expression. In marked contrast, when given as a single signal, CD28 MoAb or B7.1 and B7.2 induced FasL expression and resulted in T-cell death by apoptosis, which was dependent on the level of CD28 ligation. Furthermore, triggering of CD28 upregulated FasL and induced a marked T-cell death of previously activated normal peripheral T cells. Our results identify Fas and FasL as crucial targets of CD28 in T-cell death regulation and show that within the same cell population, depending on its engagement as a single signal or as a costimulus together with the TCR, CD28 can either induce a dose-dependent death signal or protect from cell death, respectively. These data provide important insights into the role of CD28 in T-cell homeostasis and its possible implication in neoplastic disorders.

Animals↗

PubMed1998

The human immunodeficiency virus type 1 Nef protein binds the Src-related tyrosine kinase Lck SH2 domain through a novel phosphotyrosine independent mechanism.

Primate lentiviruses encode for an unique nef gene with an essential function in both viral replication and pathogenicity in the host. The molecular basis for this function remains however poorly defined. Several Nef-binding cellular proteins are thought to be instrumental in its function. Indeed, Nef contains a proline-rich motif implicated in the binding to the Src-like tyrosine kinase Hck and also to a Ser/Thr kinase of molecular weight 62 kDa. The disruption of this motif affects the binding to both these kinases as well as viral replication. Whereas Hck is expressed in the myeloid lineage and hence may account for the nef function in infected monocytes, we and others have reported previously that Nef also interacts with the T-lymphocyte Src-kinase Lck, leading to specific cell signaling impairment. This interaction occurs through the binding of Nef to both Lck SH2 and SH3 domains. Both the proline motif and phosphorylation of Nef on tyrosine residue were proposed to account for these interactions. Here, we investigate the mechanism of Lck SH2 binding by HIV-1 Nef. Using recombinant fusion proteins to precipitate lysates, we show that although SH2 binding is dependent on phosphorylation events, it occurs in a tyrosine independent manner because it requires neither tyrosine residues in Nef nor the phosphotyrosine binding pocket from the Lck SH2 domain, hence suggesting a role for a phosphoserine or a phosphothreonine residue. Further, we show that Hck SH2 does not interact with Nef, indicating that Hck SH3 binding is sufficient for Nef binding, whereas Lck SH2 cooperate together with SH3 to allow Nef binding to a level similar to Hck SH3. Together, our results establish different mechanisms for Hck and Lck binding by HIV-1 Nef protein, and identify a novel mechanism for Src-like tyrosine kinase targeting by a viral protein.

Gene Products, nef↗

PubMed1998

HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.

Hox genes are well-known transcriptional regulators that play an essential role in directing embryonic development. Mice that are homozygous for a targeted disruption of the Hoxa10 gene exhibit uterine factor infertility. We have recently demonstrated that HOXA10 is expressed in the adult human uterus. To examine expression of HOXA10 during the menstrual cycle, Northern blot analysis and in situ hybridization were performed. Expression of HOXA10 dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implantation and increase in circulating progesterone. Expression of HOXA10 in cultured endometrial cells was stimulated by estrogen or progesterone. Stimulation of HOXA10 by progesterone was concentration-dependent within the physiologic range, and the effect of estrogen was inhibited by cycloheximide. These results identify sex steroids as novel regulators of HOX gene expression. HOXA10 may have an important function in regulating endometrial development during the menstrual cycle and in establishing conditions necessary for implantation in the human.

Cells, Cultured↗

PubMed1998

Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition.

Clinical data and animal models afford evidence for anti-leukemia immunity in humans, but the interactions critical for blast cell recognition are unresolved. Expression of B7 molecules by antigen-presenting cells (APC) provides co-stimulatory signals to T lymphocytes via CD28 and CTLA-4 which prevent the induction of alloantigen-specific tolerance. Conversely, expression of CD40 ligand by stimulated T cells activates APC via CD40. In human hematological B cell malignancies (follicular lymphoma and chronic lymphocytic leukemia), the defect in alloantigen presentation of tumoral cells can be repaired by up-regulation of B7 and other co-stimulatory molecules via CD40. We studied the role of B7 molecules in alloimmune recognition and the various ways to improve the antitumoral response on peripheral blood leukemic cells from 20 patients with a diagnosis of primary acute myeloid leukemia (AML). We focused on myelo/monocytic M4/M5 French-American-British classification subtypes which are considered as the neoplastic counterpart of normal monocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD4+ T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; interleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL-4, corresponding to a Th1 pattern. Blockade experiments showed that proliferation and IFN-gamma secretion only partially depended on B7 molecules, which in contrast had a pivotal role in IL-2 synthesis. In contrast with murine models which suggest a pivotal role for CD80/B7-1 in the immune response against AML, our data support a greater role for CD86/B7-2, in line with the baseline expression of CD86/B7-2 and lack of CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1) significantly improved IL-2 secretion but not proliferation of responding T lymphocytes, (2) increased CD54/ICAM-1 expression in three quarters of cases, (3) failed in most cases to induce CD40-specific CD80/B7-1 up-regulation, and (4) had a weak effect on CD86/B7-2 expression. These data contrast with the very efficient up-regulation of both B7 co-stimulatory molecule expression and tumoral cell alloimmune recognition following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inefficient tumor immunogenicity of primary AML cells has to be further investigated, in particular using transfection experiments of CD80/B7-1-deficient AML cell lines. From our in vitro data we conclude that B7 molecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Nonetheless, the contribution of B7 molecules to alloimmune T cell proliferation against primary AML cells in human and the way to improve it--regulation via CD40 in particular--differ from B cell malignancies and murine models, suggesting the requirement for specific strategies in the development of antitumor immunity.

Antigen Presentation↗

PubMed1998

High implantation and pregnancy rates with transfer of human blastocysts developed in preimplantation stage one and blastocyst media.

OBJECTIVE: To evaluate the proficiency of preimplantation stage one (P1) and blastocyst media in supporting human blastocyst development and to document implantation and clinical pregnancy rates from the transfer of the normally developed blastocysts. DESIGN: Retrospective clinical study. SETTING: Private IVF unit of a university-affiliated center. PATIENT(S): Twenty-eight women aged 33.7 +/- 2.9 years who underwent IVF treatment for infertility. INTERVENTION(S): Bipronucleate oocytes obtained from IVF and intracytoplasmic sperm injection were cultured in vitro with P1 and blastocyst media for 96-120 hours. One to three embryos were transferred (2.1 +/- 0.2 for the patients who became pregnant and 1.5 +/- 0.3 for those who did not become pregnant). MAIN OUTCOME MEASURE(S): Total number and percentage of developed blastocysts, frequency of blastocysts of grades A and B, and implantation and pregnancy rates. RESULT(S): From 431 oocytes retrieved, 269 bipronucleate oocytes were cultured, producing 81 blastocysts that resulted in the transfer of 54 embryos in 27 procedures. Blastocysts developed in 39.7% +/- 5.5% of the pregnant group and 30.2% +/- 4.5% of the nonpregnant group. From 15 (15/27 = 55.6%) clinical pregnancies, 18 (18/54 = 33.3%) gestational sacs were visualized. The rate of implantation in the pregnant group was 58.1% (18/31). CONCLUSION(S): These results provide evidence for the benefits of extending human embryo culture with P1 and blastocyst media for all normally fertilized embryos in vitro.

Adult↗

PubMed1998

[Hodgkin's disease in patients infected with the human immunodeficiency virus].

INTRODUCTION: Hodgkin's disease in patients infected by the human immunodeficiency virus (HIV) is still not part of the definition of acquired immune deficiency syndrome. Nonetheless, this entity has a particular presentation when compared to the disease occurring in immune-competent patients. CURRENT KNOWLEDGE AND KEY POINTS: Increased frequency (> 75%) of advanced anatomical stages and extranodular localizations (Ann Arbor system stages III and IV) has been outlined in HIV-infected patients. Mediastinal involvement is more unusual in immunocompromised than in immune-competent patients. The presence of B symptoms (fever, weight loss, nocturnal sweats) is very frequent. Finally, the predominance of mixed cellularity (type 3) characterizes Hodgkin's disease in immunocompromised patients. Due to either the immunodeficiency, antiretroviral treatments, poor hematological tolerance in response to chemotherapy, or to advanced anatomical stages, disease management may be hampered. Current therapeutical approaches often obtain complete remission; however, some deaths are still related to the disease progression to acquired immune deficiency syndrome. FUTURE PROSPECTS AND PROJECTS: From these observations, Hodgkin's disease management in HIV-infected patients relies on therapeutical approaches similar to those used for non infected patients, with some specific recommendations. Chemotherapy should be conducted in the shortest time in order to minimize chemotherapy-induced immunosuppression. Simultaneous use of antiretroviral treatment and reinforced opportunistic infection prophylaxis are of pivotal importance. Finally, the use of hematopoietic growth factors appears to be safe regarding viral replication, but still requires further evaluation.

AIDS-Related Opportunistic Infections↗

PubMed1998

Malignant plasma cell lines express a functional CD28 molecule.

The function of CD28 molecules that are present on malignant plasma cells of human myeloma cell lines (HMCL) was studied. First, myeloma cells expressed a similar density of CD28 antigen to that of normal T cells. The myeloma CD28 molecules were able to bind B7-Ig molecules as well as L cells transfected with a B7-1 cDNA, and anti-CD28 mAb inhibited the binding. Myeloma cells did not express B7-1 antigens but a low density of B7-2 antigens. The myeloma B7-2 molecules of two HMCL were able to bind CTLA-4 protein. No autocrine CD28:B7-2 activation could be evidenced as we found no spontaneous binding of the p85 subunit of PI-3 kinase to CD28 molecules. In addition, a blocking anti-CD28 mAb did not affect the IL-6-dependent or autonomous proliferation of the HMCL. The activation of myeloma CD28 molecules with or without TPA stimulation did not affect the proliferation, survival, differentiation, expression of activation antigens and cytokine receptors or cytokine production of myeloma cells. However, the triggering of myeloma CD28 molecules by B7-1 transfectant cells resulted in binding of the p85 subunit of PI-3 kinase to CD28 molecules as previously shown for T cell CD28 molecules. This expression of a large density of CD28 molecules able to bind B7 molecules might contribute to a downregulation of the immune control of myeloma cells.

B7-1 Antigen↗