Biomedical subjects

M S Sy

Publications and source records attributed to M S Sy.

At least 19 recordsLinked to original sources

PubMed1996

Oncogene-dependent expression of CD44 in Balb/c 3T3 derivatives: correlation with metastatic competence.

Oncogene-dependent regulation and tumor relatedness of CD44 expression were investigated in Balb/c 3T3 cells and their derivatives transformed with different ras oncogenes (metastatic tumor model) or the human c-sis oncogene (non-metastatic model). Ras transformants using either the Harvey or Kirsten oncogenes expressed high levels of cell surface CD44 protein that bound fluoresceinated hyaluronan (HA). Much lower levels of CD44 were expressed in parental 3T3 cells, ras- revertants generated from Kirsten-transformed cells, or c-sis transformants, confirming the significance of the ras oncogene in this upregulation. To determine whether endogenous HA regulates these parameters, hyaluronidase treatment of ras transformants exposed more cell surface CD44 to anti-CD44 antibody and increased fluoresceinated HA binding; this did not occur with 3T3 or c-sis transformants. CD44 expression and its HA-binding function were conserved in a panel of in vivo primary and lung metastatic tumor cell lines derived from ras transformants. Ras transformants also retained the ability to downregulate CD44 protein levels in confluent cultures which occurred through a translational or post-translational mechanism (as CD44 mRNA levels were not reduced). These results taken together demonstrate that ras-dependent regulation of CD44 may correlate with tumor progression and metastasis in vivo, possibly (although not exclusively) supporting CD44's importance in metastatic progression.

3T3 Cells↗

PubMed1995

The immature thymocyte is protected from N-methylnitrosourea-induced lymphoma by the human MGMT-CD2 transgene.

N-methylnitrosourea (MNU) induces thymic lymphoma in a high proportion of susceptible C57BL/6xSJL (C57/SJL) mice. Expression of the human DNA repair gene, MGMT cDNA, which encodes O6-methylguanine-DNA-methyltransferase, in transgenic mice effectively prevents MNU-induced thymic lymphomas. In this study, we determined the phenotype of thymocytes expressing the transgene and defined whether the target cell population for MNU induced lymphomas were actually those that expressed the transgene. Transgene expression was characterized by in situ hybridization for MGMT mRNA and immunohistochemistry for the human alkyltransferase protein and was compared to the phenotype of the MNU induced lymphomas. The MGMT transgene was expressed uniformly in immature cortical thymocytes that were CD4+CD8+J11d+ and to a lesser extent in the medullary thymocyte. Lymphomas were induced by single [50 or 80 mg/kg] or multiple doses [30 mg/kg x 5] of MNU to evaluate the dose response of tumor induction and protection by the MGMT-CD2 transgene. Forty-seven of the 108 treated mice developed lymphomas: 38 of 58 nontransgenic and 9 of 50 MGMT+ mice. The T-cell phenotype of thymic lymphomas was established by immunohistochemistry and FACS analysis. Most of the lymphomas were J11d+ (98%), 70% of the tumors were CD4+CD8+, 21% were CD4-CD8+, 9% were CD4-CD8-, and none were CD4-CD8-. All lymphomas in MGMT+ transgenic mice were CD4+CD8+. Since the main phenotype of MNU induced lymphomas in these mice, CD4+CD8+J11d+, is also the cell phenotype which expresses the MGMT-CD2 transgene at high levels, it appears that MGMT-induced protection has occurred in the cell target for MNU induced transformation.

Animals↗

PubMed1995

Restricted expression of T cell receptor V beta and lymphokine genes in arthritic joints of a TCR V beta a (H-2q) mouse strain-BUB/BnJ-with collagen-induced arthritis.

Type II collagen-induced arthritis (CIA) is an animal model of inflammatory polyarthritis with clinical and pathological features resembling rheumatoid arthritis (RA). We compared the expression of T cell receptor (TCR) V beta genes in T cells isolated from the inflamed joints, draining lymph nodes and the spleens of BUB/BnJ (H-2q) mice (BUB) during the early phase of CIA. We also investigated the profiles of cytokine gene expression in T cells obtained from the same tissues. We found that the expression of TCR V beta s, in arthritic joints of mice, during the early phase of the disease was limited to TCR V beta 3 and 10 gene families. In contrast, TCR V beta 4, 7, and 15 were predominant in the draining lymph nodes (LNs) and TCR V beta 2, 6, and 14 were predominant in the spleens of arthritic mice. Molecular cloning and sequence analysis revealed that the T cell populations in the arthritic joints were oligoclonal as determined by the limited N-D-N region diversity observed in the sequenced clones. These results demonstrate, for the first time, that (1) joint infiltrating T cells in TCR V beta a genotype mice use a restricted repertoire of TCR V beta genes; (2) there was oligoclonal expansion of infiltrating T cells in arthritic joints in mice with collagen-induced arthritis. Our results on cytokine gene expression in the arthritic joints of BUB mice indicate that Th-1-like T cell derived cytokines may be the predominant cytokines in the arthritic joints as illustrated by the presence of transcripts for IL-2 and IFN-gamma but not IL-4. In summary, our results provide evidence that T cells with restricted specificities, and more specificially, Th-1 type T cells, are crucial in the early phase of collagen induced arthritis in mice.

Amino Acid Sequence↗

PubMed1994

In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes.

Development of contact hypersensitivity in mice depends on the migration of Langerhans cells from the epidermis to regional lymph nodes. Since ICAM-1 and LFA-1 play important roles in leukocyte migration, we sought to determine whether in vivo administration of anti-ICAM-1 and anti-LFA-1 antibodies would inhibit contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Twenty-four hours after contact sensitization of mice with FITC, a brightly FITC-stained Ia+ population of dendritic cells capable of stimulating a FITC-specific Ia-restricted T-cell hybridoma was readily detected in their draining lymph nodes. Animals treated with anti-Ia mAb, which depletes Ia+ cells in lymph nodes and spleen but not Ia+ Langerhans cells in the epidermis, had normal numbers of FITC-bearing Ia+ cells capable of stimulating the T-cell hybridoma. Dendritic lymph node cells from mice treated with anti-ICAM-1 and anti-LFA-1 mAb were devoid of brightly FITC-stained cells and cells capable of stimulating the FITC-specific T-cell hybridoma. The combination of anti-ICAM-1 and anti-LFA-1 mAb completely inhibited the induction of contact hypersensitivity to FITC. Animals treated with anti-ICAM-1 or anti-LFA-1 monoclonal antibodies alone had significantly reduced (by 79 and 36%, respectively) numbers of brightly stained cells capable of stimulating the hybridomas. These data suggest that the adhesion molecules, ICAM-1 and LFA-1, play a significant role in contact hypersensitivity-induced migration of Langerhans cells to regional lymph nodes. The immunomodulatory effects of anti-adhesion molecule antibodies in vivo may be in part due to their effects on antigen-presenting cell migration.

Animals↗

PubMed1994

Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody.

CD44 is a M(r) 90,000 surface glycoprotein believed to be involved in cell adhesion and migration. We investigated the role of CD44 in tumor growth and metastasis using human melanoma cell lines SMMU-1 and SMMU-2. Both SMMU-1 and SMMU-2 form tumors in the s.c. tissues when injected s.c. in SCID mice but only SMMU-2 metastasizes. Approximately one-half of SCID mice receiving injections of SMMU-2 s.c. develop metastatic tumors. SMMU-2 but not SMMU-1 expresses high levels of the hematopoietic form of CD44 and binds fluorescence-conjugated hyaluronic acid in vitro. GKW.A2 is a monoclonal antibody specific for human CD44 that can completely inhibit the binding of hyaluronic acid to SMMU-2 tumor cells in vitro. Moreover, in vivo injection of GKW.A3 inhibited the growth and metastatic potential of SMMU-2 tumor cells. Administration of GKW.A3 i.v. 1 week after s.c. tumor injection did not inhibit local tumor development but inhibited the formation of metastatic tumors and prolonged animal survival. Therefore, interactions between CD44 on tumor cells and its ligands in vivo may be necessary for tumor growth and metastasis.

Animals↗

PubMed1994

Effective tumor vaccine generated by fusion of hepatoma cells with activated B cells.

Fusion of BERH-2 rat hepatocellular carcinoma cells with activated B cells produced hybrid cells that lost their tumorigenicity and became immunogenic. Syngeneic rats injected with BERH-2-B hybrid cells became resistant to challenge with parental BERH-2 cells, and rats with established BERH-2 hepatomas were cured by subsequent injection of BERH-2-B cells. Both CD4+ and CD8+ cells were essential for the induction of protective immunity; however, only CD8+ cells were required for the eradication of BERH-2 tumors. The generation of hybrid tumor cells that elicit antitumor immune responses may be a useful strategy for cancer immunotherapy.

Animals↗

PubMed1994

Potential use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer.

Soluble CD44 is present in the serum of normal individuals (2.7 +/- 1.1 nM). The concentration of soluble CD44 in the serum is elevated in patients with advanced gastric (24.2 +/- 9.8 nM) or colon cancer (30.8 +/- 11 nM). Serum CD44 concentration correlated with tumor metastasis and tumor burden. Surgical resection of tumors resulted in decreases in serum CD44 levels. By Western blot analysis, monoclonal anti-CD44 antibody reacted with a major protein with molecular weight between 130,000 and 190,000. In addition, two proteins with molecular weights of 72,000 and 80,000 can also be identified. Therefore, different CD44 isoforms may be present in the serum of cancer patients. Serum CD44 concentrations may be an indicator of tumor burden and metastasis in patients with malignant diseases.

Adenocarcinoma↗

PubMed1994

Disruption of T lymphocyte reappearance in anti-Thy-1-treated animals in vivo with soluble CD44 and L-selectin molecules.

We used polyclonal rabbit anti-Thy-1 antiserum to eliminate T lymphocytes in the peripheral blood, lymph nodes, and spleens but not in the thymus of normal mice. T lymphocytes began to reappear in the peripheral lymphoid compartments 2 weeks after termination of the treatment. By 4 weeks, the numbers of peripheral T lymphocytes had recovered to normal levels. We found that injection of recombinant soluble forms of human CD44 or L-selectin but not human CD8 molecules delayed the reappearance of peripheral T lymphocytes in anti-Thy-1-treated mice. This delay in recovery most likely reflects the ability of these soluble receptors to interfere with lymphocyte migration in vivo. Our results provide in vivo evidence that CD44 and L-selectin regulates lymphocyte trafficking and suggest that soluble forms of both molecules provide useful tools for the study of lymphocyte migration in vivo.

Animals↗

PubMed1994

Palmitoylation of CD44 interferes with CD3-mediated signaling in human T lymphocytes.

We studied the interactions between CD44 and four different monoclonal anti-CD44 antibodies. All four monoclonal anti-CD44 antibodies studied (P3H9, Bu52, IM.7, and GKW.A3) act in synergy with human anti-CD2 antibodies in stimulating normal human peripheral blood lymphocytes to proliferate. GKW.A3 and IM.7 but not P3H9 or Bu52 inhibited the proliferation of normal human peripheral blood lymphocytes stimulated by anti-CD3. Interestingly, only GKW.A3 and IM.7 stimulated the incorporation of [3H]palmitic acid and palmitoylation of CD44 molecules by normal human peripheral blood lymphocytes. The two monoclonal anti-CD44 antibodies (P3H9 and Bu52) that failed to inhibit anti-CD3 induced proliferation also failed to induce the incorporation of [3H]palmitic acid. More importantly, the inhibitory effects of GKW.A3 were reversed in the presence of cerulenin, an inhibitor of protein palmitoylation. Therefore, palmitoylation of CD44 may interfere with anti-CD3 mediated signaling pathways. These data support the hypothesis that palmitoylation of cell surface receptors may play an active role in receptor and receptor interactions and signal transduction in normal human T lymphocytes.

Antibodies, Monoclonal↗

PubMed1994

Trinitrophenol reactive T-cell hybridomas recognize antigens that require antigen processing.

Protein antigens must be taken up, processed, and displayed on the surface of antigen-presenting cells in association with major histocompatibility complex molecules before they can be recognized by T cells. Whether recognition of the haptens used to study allergic contact hypersensitivity in murine models similarly requires processing has not been determined. We analyzed whether presentation of trinitrophenol to trinitrophenol reactive T-cell hybridomas requires antigen processing by studying the effects of inhibitors of antigen processing and presentation on the ability of a syngeneic B-cell tumor (A20) to present trinitrophenol to a series of interleukin-2 producing, trinitrophenol specific, major histocompatibility complex class II-restricted T-cell hybridomas. The ability of trinitrophenol modified A20 cells to stimulate the hybridomas was completely inhibited by monoclonal, anti-trinitrophenol, or anti-Ia antibodies and was significantly reduced by paraformaldehyde fixation immediately after trinitrophenol modification. Trinitrophenol-modified A20 cultured at 37 degrees C for 2 h prior to fixation was significantly more effective at stimulating the hybridomas than trinitrophenol-modified A20 fixed immediately. The ability of A20 to present trinitrophenol was inhibited by chloroquine. Paraformaldehyde fixation and chloroquine treatment had similar effects on the ability of trinitrophenol modified lymph node dendritic cells to stimulate the trinitrophenol specific hybridomas. Paraformaldehyde fixation and chloroquine treatment had similar effects on the ability of A20 cells to present ovalbumin to ovalbumin-specific hybridomas as they had on the ability of trinitrophenol modified A20 cells to present trinitrophenol to the trinitrophenol specific hybridomas. One of seven T-cell hybridomas responded to trinitrophenol modified ovalbumin but not other trinitrophenol modified proteins. These results suggest that, at least in part, T cells in the contact hypersensitivity response to trinitrophenol recognize antigens that require processing and that trinitrophenol modified proteins can be recognized.

Albumins↗

PubMed1993

Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis.

In patients with glomerulonephritis widespread crescents are associated with a poor prognosis. Crescent formation appears to depend on the migration of mononuclear cells into Bowman's space, and therefore the interaction between leukocytes and glomerular endothelium may be a critical event in the genesis of crescents. We performed the present study to determine the effects of mouse monoclonal antibodies to the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in a model of crescentic glomerulonephritis in Wistar-Kyoto rats, induced by immunization with bovine glomerular basement membrane (GBM). By 10-14 d after immunization, the rats had developed circulating anti-GBM antibodies, reactive with the alpha 3 chain of type IV collagen (the Goodpasture antigen), accompanied by proteinuria, accumulation of rat immunoglobulin (Ig)G in the GBM, increased expression of ICAM-1 by glomerular endothelial cells, infiltration of glomerular tufts with LFA-1+ T cells and monocyte/macrophages, and early crescents. At 5 wk all rats had diffuse fibrocellular crescents, glomerular sclerosis, and tubulointerstitial damage. All rats developed severe renal insufficiency and died by 5 or 6 wk. The administration of monoclonal antibodies to rat ICAM-1 and LFA-1 markedly decreased the severity of the renal disease. In a group of rats injected three times a week with the monoclonal antibodies, from 2 d before immunization with GBM to day 14, glomerular abnormalities and proteinuria were virtually absent at day 14; even at 5 wk glomerular disease was quite mild, with only slight crescent formation and with only a mild decrease in renal function. When treatment was continued until 5 wk, the beneficial effects were even more marked, with virtual absence of crescents and with preservation of normal renal function. In a group of rats in which treatment was initiated on day 14, shortly after the appearance of glomerular abnormalities, progression of the disease was appreciably retarded, and the decrease in renal function was inhibited. The kidneys of rats treated from days -2 to 14 with antibodies to ICAM-1 and LFA-1 showed bright linear staining for rat IgG along the GBM, which did not differ in intensity from that seen in untreated rats. Furthermore, the titers of anti-GBM antibodies at 2 wk in treated rats were not lower than that seen in most of the untreated rats. There was, however, moderate reduction of anti-GBM antibodies at 5 wk in the treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Anti-CD3:anti-IL-2 receptor bispecific monoclonal antibody. Targeting of activated T cells in vitro.

T cells are major mediators of graft rejection and many autoimmune diseases. During the Ag recognition process, T cells often become activated. We tested the hypothesis that an anti-CD3:anti-CD25 (CD3,25) bispecific mAb (BSMAB) can effectively and selectively target activated T cells. By flow cytometric analysis, the CD3,25 BSMAB was shown to bind avidly to activated T cells that coexpress CD3 and CD25 (p55 chain of the IL-2R), achieving higher levels than the parent anti-CD3 and anti-CD25 mAb. It bound only weakly to unstimulated T cells. The CD3,25 BSMAB effectively redirected CTL to lyse CD25-bearing PHA-stimulated T lymphoblasts and the IL2-dependent CTLL tumor cell line in chromium release assays. It was highly effective in blocking MLR as shown by inhibition of [3H]TdR incorporation. However, the CD3,25 BSMAB has a low potential to activate resting T cells, as it induced only minimal [3H]TdR incorporation even in the presence of exogenous IL-2. In the absence of exogenous IL-2, the CD3,25 BSMAB was unable to induce [3H]TdR incorporation. In contrast, the parent anti-CD3 mAb induced a high degree of incorporation. In summary, the CD3,25 BSMAB selectively targets activated CD25-expressing T cells and lymphomas although maintaining a low activation potential for unstimulated T cells, potentially advantageous properties that can be exploited for immunotherapy.

Animals↗

PubMed1993

Monoclonal anti-CD44 antibody acts in synergy with anti-CD2 but inhibits anti-CD3 or T cell receptor-mediated signaling in murine T cell hybridomas.

We investigated the effects of anti-murine CD44 monoclonal antibodies on the activation of antigen-specific T cell hybridomas. Anti-murine CD44 antibodies by themselves did not induce the production of IL-2 by antigen-specific T cell hybridomas. However, anti-murine CD44 monoclonal antibodies were able to either inhibit or enhance the production of IL-2, depending on the other monoclonal antibodies used as comitogenic stimuli. When a T cell hybridoma was activated by antigen and antigen-presenting cells or anti-CD3 antibodies, addition of anti-CD44 antibodies inhibited IL-2 production. In contrast, monoclonal anti-CD44 antibodies acted in synergy with anti-human CD2 antibodies in stimulating a murine T cell hybridoma stably transfected with the human CD2 gene to produce IL-2. Therefore, cross-linking of surface CD44 is able to deliver either a positive or a negative signal in murine antigen-specific T cell hybridomas. One of the ligands for CD44 is hyaluronic acid. Hyaluronic acid in vitro significantly increased the activation of murine T cell hybridomas. Hyaluronic acid itself was mitogenic for T cell hybridomas. Therefore, in addition to being an adhesion molecule, CD44 functions as a signal-transducing molecule on murine T cell hybridomas.

Animals↗

PubMed1992

Inhibition of tumor growth in vivo with a soluble CD44-immunoglobulin fusion protein.

CD44H is the principal cell surface receptor for hyaluronate, which is a major glycosaminoglycan of the extracellular matrix. Expression of CD44H is enhanced in a variety of malignant tumors and correlates with tumor aggressiveness, supporting the notion that interaction between CD44H and hyaluronate may play an important role in tumor growth and dissemination. In this report we show that in vivo tumor formation by human lymphoma Namalwa cells, stably transfected with CD44H, can be suppressed by a soluble human CD44H-immunoglobulin fusion protein. Disruption of the interaction between CD44H and its physiologic ligands may provide a novel strategy for controlling tumor growth in vivo.

Animals↗

PubMed1991

Distinct effects of two CD44 isoforms on tumor growth in vivo.

Tumor growth is dependent in part on interactions between tumor cells and the extracellular matrix of host tissues. Expression of the cell surface glycoprotein CD44/Pgp-1, which mediates cell-substrate interactions is increased in many types of malignancies, but the role of CD44 in tumor growth is largely undefined. Recently, two isoforms of CD44 have been identified: an 80-90 kD form, which has high affinity for cell bound hyaluronate and a 150 kD form which does not mediate attachment to hyaluronate-coated surfaces. In this work, human B cell lymphoma cells stably transfected with cDNA clones encoding either of the two CD44 isoforms were compared for tumorigenicity and metastatic potential in nude mice. Expression of the 80-90 kD form but not the 150 kD form of CD44 greatly enhanced both local tumor formation and metastatic proclivity of the lymphoma cells. Our results suggest that CD44 polypeptides may play an important role in regulating primary and metastatic tumor development in vivo.

Animals↗

PubMed1991

The B lymphocyte adhesion molecule CD22 interacts with leukocyte common antigen CD45RO on T cells and alpha 2-6 sialyltransferase, CD75, on B cells.

Functional maturation of B lymphocytes correlates with expression of the B lineage-specific cell surface glycoprotein CD22. Two CD22 polypeptides have been characterized and suggested to play a role in B cell-B cell interaction as well as in B cell adhesion to monocytes. In this work we provide evidence that CD22 is directly involved in the cognate interaction between B and T cells. One of the two CD22 polypeptides, CD22 beta, interacts with a specific ligand on a subpopulation of CD4+ T cells. Our results suggest that the T cell ligand of CD22 is CD45RO, an isoform of the leukocyte common antigen class of phosphotyrosine phosphatases associated with the helper T cell phenotype. We further demonstrate that CD22 recognizes a second ligand, CD75, expressed predominantly on activated B cells and shown to be a cell surface alpha 2-6 sialyltransferase.

Antibodies, Monoclonal↗

PubMed1991

Molecular analysis of the interaction of p56lck with the CD4 and CD8 antigens.

The CD4 and CD8 antigens on the surface of T cells appear to bind to major histocompatibility complex (MHC) class II and I antigens, respectively. These antigens also synergize with the Ti(TcR)/CD3 complex in the potentiation of T-cell proliferation. Our earlier work demonstrated that the CD4 and CD8 receptors are coupled to a protein-tyrosine kinase termed p56lck from normal and transformed T lymphocytes. The p56lck protein is a member of the src family and its homology with receptor-kinases such as the epidermal growth factor receptor (EGFR) make it an important candidate in signal transduction. In this paper, we show in transfectants that p56lck interacts with the cytoplasmic tail of the CD4 antigen. Murine p56lck can interact across species with the human CD4 receptor. Furthermore, peptide competition studies showed that a specific sequence within the cytoplasmic tail of CD4 interacts with the kinase. Cysteine residues also appear to play key roles in this interaction. Lastly, we show biochemically that the CD4:p56lck complex can physically associate with the epsilon chain of the CD3 complex on HPB-ALL transformed T cells. This interaction may provide a bridge by which events related to ligand binding to Ti(TcR)/CD3 may trigger T cells via the CD4/CD8:p56lck complex.

Amino Acid Sequence↗

PubMed1990

Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium.

PMA causes rapid down-modulation of CD4 molecules on murine immature thymocytes, human PBL, and CD4-positive human tumor cell lines, but not on murine peripheral lymphocytes. The mechanisms of phorbol ester-induced down modulation of CD4 molecules, however, have not been elucidated. To determine how PMA down-modulates CD4 expression by T lymphocytes, we studied the ability of inhibitors of protein kinase C, calmodulin, actin, and tubulin to block PMA-induced modulation of CD4 in several murine and human cell types. We also tested the ability of intracellular and extracellular calcium chelators to block CD4 internalization. There was marked variability in the degree of PMA-induced down-modulation of CD4 among various cell types. The effects of PMA on CD4 expression were greater for murine thymocytes, for human PBL, and for the human lymphoblastic leukemia cell line, MOLT-3, than for any of the other cell types studied. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked phosphorylation but not internalization of CD4 molecules induced by PMA. Therefore, phosphorylation of CD4 molecules by protein kinase C is not required for the internalization of the molecules. Internalization was blocked by both inhibitors of calmodulin, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, and trifluoperazine. PMA-induced internalization of CD4 was blocked by Quin-2 AM, which chelates intracellular calcium. EGTA, which chelates extracellular calcium, did not block internalization. Inhibitors of actin or tubulin did not block internalization. These results suggest that PMA-induced modulation of CD4 can occur in the absence of phosphorylation of the CD4 molecules and is calmodulin and intracellular calcium dependent.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗