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Biomedical subjects

G Rowden

Publications and source records attributed to G Rowden.

At least 19 recordsLinked to original sources
PubMed2006

Effects of alveolar macrophage depletion on liposomal vaccine protection against respiratory syncytial virus (RSV).

Little is known about the identities and roles of antigen-presenting cells upon exposure to antigens of respiratory syncytial virus (RSV). Here, we focused on elucidating the importance of alveolar macrophages in conferring protective immunity in mice administered a liposome-encapsulated recombinant fragment of the RSV G protein. Mice were depleted of alveolar macrophages by intranasal inoculation of liposome-encapsulated dichloromethylenediphosphonic acid (DMDP). Mice depleted of alveolar macrophages prior to immunization developed reduced levels of serum RSV-neutralizing antibody and showed dramatically impaired protection against RSV challenge. The severity of interstitial inflammation was also markedly reduced in macrophage-depleted mice. In conclusion, this study demonstrates a pivotal role for alveolar macrophages during exposure to liposome-encapsulated RSV antigen in initiating both protective and histopathological responses against RSV.

Animals↗
PubMed2001

The dendritic cell cytoskeleton is critical for the formation of the immunological synapse.

The binding of a T cell to an APC results in T cell actin cytoskeletal rearrangement leading to the formation of an immunological synapse. The APC cytoskeleton has been thought to play a passive role in this process. In this study, we demonstrate that dendritic cells (DC), unlike other APC, actively polarize their actin cytoskeleton during interaction with T cells. DC cytoskeletal rearrangement was critical for both the clustering and the activation of resting T cells. This study provides compelling evidence that the APC cytoskeleton plays an active role in the immunological synapse and may explain the unique ability of DC to activate resting T cells.

Actins↗
PubMed2001

Fascin is involved in the antigen presentation activity of mature dendritic cells.

Maturation of dendritic cells (DC) is critical to their development into potent APCs. Upon maturation, DC up-regulate the expression of MHC class II as well as costimulatory and adhesion molecules, all of which are important in Ag presentation. In addition, they undergo structural changes characterized by the expression of numerous long dendrites. Fascin is an actin-bundling protein that has been reported to be important for the development of dendrites. In this study, we evaluated fascin expression and function during DC maturation into potent APC. In vitro, treatment of bone marrow-derived DC (BM-DC) with GM-CSF resulted in increased levels of fascin expression. This increase correlated directly with an increase in MHC class II and B7-2 expression. Fascin expression was decreased by the addition of TGF-ss and increased by the addition TNF-alpha to the culture. These cytokines suppress or enhance DC maturation, respectively. Increased levels of fascin expression were found to correlate with increased APC activity in a one-way MLR. Specific inhibition of fascin expression, using antisense oligonucleotides, markedly reduced this APC allostimulatory activity. These data demonstrate that fascin expression correlates with DC maturation into APC, and it plays a significant role in the ability of DC to function as APC. This observation is the first evidence linking fascin-mediated dendrite formation with the APC activity of DC.

Actins↗
PubMed2001

Cytokine induction of a human acute myelogenous leukemia cell line (KG-1) to a CD1a+ dendritic cell phenotype.

Dendritic cells (DC) are highly specialized antigen-presenting cells located in many nonlymphoid tissues, and Langerhans cells (LC), a specialized form of DC, are found in the skin. LC as antigen-presenting cells play a critical role in the induction of allergic contact dermatitis. LC research is difficult because few LCs can be isolated from human skin, so efforts have focused on obtaining DCs from alternative sources. Mononuclear cells from peripheral blood and CD34+ stem cells from human cord blood and marrow can be induced to form phenotypic and functional DCs, but experiments of this type are expensive and the DC yield is low. We report here the induction of the myeloid leukemia cell line (KG-1) to a DC morphology and phenotype by culturing the cells in a defined cytokine cocktail. Morphologically, the KG-1-derived DCs are large irregularly shaped cells with prominent dendritic processes and hair-like cytoplasmic projections. Phenotypically, the KG-1-derived DCs lack lineage-specific markers, and express MHC class II, costimulatory molecules CD80 and CD86, and CD83. Functionally, KG-1-derived DCs are capable of phagocytosing latex microspheres and are able to induce a potent allogeneic T-cell response. Within the KG-1-derived DCs, a subpopulation maintains the DC phenotype and morphology described above but further develops CD1a+ marker expression similar to that of resident skin-derived LCs. These findings illustrate that phenotypic, morphologic and functional DCs can be derived from the KG-1 cell line.

Antigens, CD1↗
PubMed2001

Resistance training improves single muscle fiber contractile function in older women.

The purpose of this study was to 1) examine single cell contractile mechanics of skeletal muscle before and after 12 wk of progressive resistance training (PRT) in older women (n = 7; 74 +/- 2 yr) and 2) to compare these results to our previously completed single cell PRT work with older men (n = 7; 74 +/- 2 yr) (Trappe S, Williamson D, Godard M, Porter D, Rowden G, and Costill D. J Applied Physiol 89:143--152, 2000). Knee extensor PRT was performed 3 days/wk at 80% of one-repetition maximum. Muscle biopsies were obtained from the vastus lateralis before and after the PRT. Chemically skinned single muscle fibers (n = 313) were studied at 15 degrees C for peak tension (P(o)), unloaded shortening velocity (V(o)), and power. Due to the low number of hybrid fibers identified post-PRT, direct comparisons were limited to MHC I and IIa fibers. Muscle fiber diameter increased 24% (90 +/- 2 to 112 +/- 6 microm; P < 0.05) in MHC I fibers with no change in MHC IIa fibers. P(o) increased (P < 0.05) 33% in MHC I (0.76 +/- 0.04 to 1.01 +/- 0.09 mN) and 14% in MHC IIa (0.73 +/- 0.04 to 0.83 +/- 0.05 mN) fibers. Muscle fiber V(o) was unaltered in both fiber types with PRT. MHC I and IIa fiber power increased (P < 0.05) 50% [11 +/- 2 to 17 +/- 2 microN. fiber length (FL). s(-1)] and 25% (40 +/- 8 to 51 +/- 6 microN. FL. s(-1)), respectively. However, when peak power was normalized to cell size, no pre- to postimprovements were observed. These data indicate that PRT in elderly women increases muscle cell size, strength, and peak power in both slow and fast muscle fibers, which was similar to the older men. However, in contrast to the older men, no change in fiber V(o) or normalized power was observed in the older women. These data suggest that older men and women respond differently at the muscle cell level to the same resistance-training stimulus.

Aged↗
PubMed2000

Effect of resistance training on single muscle fiber contractile function in older men.

The purpose of this study was to examine single cell contractile mechanics of skeletal muscle before and after 12 wk of progressive resistance training (PRT) in older men (n = 7; age = 74 +/- 2 yr and weight = 75 +/- 5 kg). Knee extensor PRT was performed 3 days/wk at 80% of one-repetition maximum. Muscle biopsy samples were obtained from the vastus lateralis before and after PRT (pre- and post-PRT, respectively). For analysis, chemically skinned single muscle fibers were studied at 15 degrees C for peak tension [the maximal isometric force (P(o))], unloaded shortening velocity (V(o)), and force-velocity parameters. In this study, a total of 199 (89 pre- and 110 post-PRT) myosin heavy chain (MHC) I and 99 (55 pre- and 44 post-PRT) MHC IIa fibers were reported. Because of the minimal number of hybrid fibers identified post-PRT, direct comparisons were limited to MHC I and IIa fibers. Muscle fiber diameter increased 20% (83 +/- 1 to 100 +/- 1 microm) and 13% (86 +/- 1 to 97 +/- 2 microm) in MHC I and IIa fibers, respectively (P < 0.05). P(o) was higher (P < 0.05) in MHC I (0.58 +/- 0.02 to 0.90 +/- 0.02 mN) and IIa (0.68 +/- 0.02 to 0.85 +/- 0.03 mN) fibers. Muscle fiber V(o) was elevated 75% (MHC I) and 45% (MHC IIa) after PRT (P < 0.05). MHC I and IIa fiber power increased (P < 0.05) from 7.7 +/- 0.5 to 17.6 +/- 0.9 microN. fiber lengths. s(-1) and from 25.5 to 41.1 microN. fiber lengths. s(-1), respectively. These data indicate that PRT in elderly men increases muscle cell size, strength, contractile velocity, and power in both slow- and fast-twitch muscle fibers. However, it appears that these changes are more pronounced in the MHC I muscle fibers.

Aged↗
PubMed2000

L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells.

Prolactin (PRL) inhibits apoptosis and stimulates proliferation of the PRL-dependent rat Nb2 lymphoma cell line by divergent signaling pathways. Nitric oxide (NO) was recently identified as a downstream regulator of PRL action, and as an inhibitor of apoptosis in immune cells. In the present study, the role of NO in PRL-regulated Nb2 cell function was investigated. Nb2 cells expressed the endothelial nitric oxide synthase (eNOS) isoform, whereas neuronal NOS (nNOS) and inducible NOS (iNOS) mRNAs were undetectable. The eNOS mRNA was abundantly expressed in PRL-deprived, growth-arrested cells but decreased by at least 3-fold at 3-24 h following PRL treatment. Downregulation of eNOS was not accompanied by a corresponding decrease in the eNOS protein, the level of which remained constant for at least 24 h after PRL treatment. PRL had no effect on the phosphorylation state or subcellular redistribution of the eNOS enzyme, or on production of NO by Nb2 cells. However, increasing concentrations of L-arginine (NOS substrate) alone increased NO production in these cells and significantly enhanced PRL-stimulated cell proliferation. NO releasers (SNAP, DEA/NO, SIN-1) also significantly enhanced Nb2 cell proliferation in the presence of a submaximal dose of PRL (0.125 ng/ml). In the absence of PRL, the NO releasers alone promoted cell survival and maintained a viable cell density significantly higher than that of untreated PRL-deprived cells. L-arginine or the NO releaser DEA/NO alone significantly inhibited apoptosis in Nb2 cells deprived of PRL for 5 days. Expression of the anti-apoptotic gene bcl-2, which was stimulated within 1 h by PRL, was upregulated by L-arginine or DEA/NO alone at 2 h and 8 h, respectively. These findings suggest that NO produced by eNOS inhibits apoptosis and promotes the survival of growth-arrested Nb2 lymphoma cells via a prolactin-independent, Bcl-2-mediated pathway.

Animals↗
PubMed1998

Drug-metabolizing enzymes in rat liver myofibroblasts.

The myofibroblast is considered to be a key component in the pathogenesis of hepatic fibrosis. There is a need for therapeutic intervention in hepatic fibrosis, and, to date, the number of efficacious anti-fibrotic drugs is negligible. At best, the current therapeutic modalities reduce liver enzymes, an indicator of liver damage, but cannot reduce or prevent fibrosis. We have described the anti-fibrotic effect of pentoxifylline in an experimental model of hepatic fibrosis. Evidence suggests that, in addition to pentoxifylline itself, at least two of the metabolites of pentoxifylline are of therapeutic interest. We have reported that one of these metabolites (M-1) has a biological activity similar to that of its parent drug. The second metabolite (M-1R) has been reported to be more potent than the parent drug. Recent evidence suggests that inhibition of cytochrome P450 1A2 (CYP1A2) results in higher levels of pentoxifylline and M-1 and may be responsible for the production of the novel, potent metabolite (M-1R). We therefore investigated whether the myofibroblast, the cell with a crucial role in fibrosis, contains drug-metabolizing enzymes and thus may play a critical role in the anti-fibrotic actions of pentoxifylline. Our results showed that myofibroblasts contain aryl hydrocarbon hydroxylase activity, ethoxyresorufin O-deethylase activity, and methoxyresorufin O-demethylase activity. The results presented here also indicate that aryl hydrocarbon hydroxylase and methoxyresorufin O-demethylase activities can be increased by treatment of cells with dibenzanthracene, an inducer of CYP1A activities.

Animals↗
PubMed1997

Establishment and characterization of a renal cell carcinoma line from a patient with von Hippel-Lindau syndrome.

It is not known how the von Hippel-Lindau (VHL) gene and the, as yet unidentified, renal cell carcinoma (RCC) gene(s) interact to result in RCC; nor is it known if mutations in both, or all genes are necessary for this progression. The availability of a RCC cell line from a VHL patient would be useful in studies comparing sporadic RCC with RCC resulting from VHL syndrome; and for determining the relationship or interaction of the RCC gene with the VHL gene to produce a common tumor type. This paper describes the isolation and characterization of a renal cell carcinoma cell line derived from a patient with von Hippel-Lindau disease. The line is epithelial in origin and the genome contains a familial mutation in the VHL gene. Tissue culture studies indicate that this cell line, although immortalized, is not fully transformed. Chromosomal analysis performed on cells derived from disseminated primary tumor cells revealed no detectable chromosomal abnormalities. However, analysis performed on cells at passages 9, 19, 41, and 79 showed both numerical and structural chromosomal changes. The cytogenetic profile of this cell line demonstrated a number of abnormalities known to be associated with RCC from patients with and without VHL syndrome.

Adult↗
PubMed1997

Immunophenotyping of insulitis in control and essential fatty acid deficient mice treated with multiple low-dose streptozotocin.

Multiple injections of low-dose streptozotocin induce lymphocytic insulitis and autoimmune diabetes in male CD-1 mice. Prior to the onset of insulitis, macrophages infiltrate the islets (single cell insulitis) and presumably help initiate the lymphocytic response directed at streptozotocin-induced neoantigens on islet beta cells. Essential fatty acid deficiency ameliorates the lymphocytic insulitis and prevents diabetes in this model. We hypothesize that essential fatty acid deficiency, which perturbs eicosanoid pathways and blocks the production of inflammatory mediators such as leukotriene B4, might prevent or diminish the single cell insulitis and, thus, abrogate the lymphocytic response. The purpose of the study was to determine whether essential fatty acid deficiency causes any differences in the immunophenotype or the time course of single cell insulitis or insulitis after low-dose streptozotocin. Three to five essential fatty acid deficient and 3-5 control mice were treated with low-dose streptozotocin and killed on days 0, 3, 5, 8, 10, 12 and 15. Frozen sections of the pancreata were stained using an immunoperoxidase method with antibodies against mouse macrophages, CD4T-lymphocytes and CD8 T-lymphocytes. Sections were assessed for the presence and severity of single cell insulitis and insulitis. Based on cell counts in the most severely involved islet from each pancreas, there was no difference in the single cell insulitis in control and essential fatty acid deficient mice. Islets from control pancreata had a higher mean grade of lymphocytic insulitis. These findings suggest that autoimmune diabetes following low-dose streptozotocin in control mice is the result of both lymphocytic and histiocytic infiltrates with subsequent beta-cell destruction. Our results do not support the hypothesis that the protective effect of essential fatty acid deficiency is due to diminished influx of macrophages into the islets. It is, however, possible that essential fatty acid deficiency deleteriously affects macrophage function and, thus, blunts the lymphocytic response.

Animals↗
PubMed1997

Immunophenotyping fish-to-mouse islet xenograft rejection: a time course study.

UNLABELLED: Tilapia islets, Brockmann bodies (BBs), transplanted under the kidney capsule (KC) of diabetic nude mice provide long-term normoglycemia, but, when transplanted into euthymic mice, reject in about one week. OBJECTIVES: The present study characterizes the cellular infiltrates at several time points during the xenograft rejection process. METHODS: Tilapia BBs were harvested, fragmented, cultured overnight, and then transplanted under the KC of streptozotocin-diabetic Balb/c mice. Glucose levels were measured daily until the mice were killed at 1 (n = 2), 2 (n = 2), 3 (n = 3), and 5 days (n = 3) post transplantation and at the time of BB graft rejection (n = 6). Serial frozen sections of graft-bearing kidneys were stained for murine macrophages (MOMA-2, F4/80, M170), CD4+ (L3T4) T-cells (YTS 191.1), and CD8+ (Ly-2) T-cells (YTS 169.4) by indirect immunoperoxidase; the presence of granulocytes and plasma cells was assessed with H&E stained sections. RESULTS: At 1 day, the grafts have undergone some central necrosis with macrophage infiltration. By 2 days, these changes are very well-developed and granulocytes, almost exclusively eosinophils, begin to surround the graft. At 3 days, rare CD4+ and CD8+ T-cells are seen at the graft kidney interface. Macrophages massively infiltrate the necrotic foci and pepper the graft. At 5 days and at rejection, macrophages and eosinophils predominated in the center of rejecting grafts while CD8+ T-cells and CD4+ T-cells were present at the periphery. Plasma cells were rare. CONCLUSION: We conclude that cell-mediated processes and eosinophils play roles in the rejection of cellular xenografts across this very wide phylogenetic barrier.

Animals↗
PubMed1996

Apoptosis is the mode of keratinocyte death in cutaneous graft-versus-host disease.

BACKGROUND: Satellite cell necrosis is a histopathologic hallmark of cutaneous graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. Although this interaction of lymphocytes with keratinocytes has features of immune cytolytic destruction, the details of the process are not known. OBJECTIVE: Our purpose was to investigate whether apoptosis is involved in the process of GVHD. METHODS: We used TdT-mediated dUTP-biotin nick end labeling (TUNEL) technique with biotinylated nucleotides. Formalin-fixed, paraffin-embedded sections from skin biopsy specimens of patients with GVHD and normal skin were studied. RESULTS: Labeling of scattered individual keratinocytes in the epidermis and adnexal epithelium undergoing cytolytic degeneration and a proportion of the adjacent lymphocytes was noted in all specimens of GVHD. CONCLUSION: The positive staining of keratinocytes by the TUNEL method indicates that cell destruction in cutaneous GVHD involves apoptosis.

Adolescent↗
PubMed1996

Macrophages, but not Langerhans cell-like cells of dendritic lineage, express the CD36 molecule in normal human dermis: relevance to downregulatory cutaneous immune responses?

The CD36 molecule has been shown to be associated with subsets of peripheral blood monocyte/macrophages and, in cells isolated from either ultraviolet (UV)-irradiated or diseased skin, to induce downregulatory immune responses. Although macrophages are certainly present within normal human dermis, whether they normally express CD36 is still a matter of debate. In this study, we investigated dermal CD36-expressing macrophages in situ using the gold immunoelectron microscopic technique on tissue ultracryosections. This is a very sensitive and specific method, and its results clearly reflect the in vivo immunophenotypic constitutive situation. Macrophages in normal human dermis were variously shaped from round to dendritic and were localized either immediately beneath the epidermis, in perivascular areas, or in intervascular zones. Macrophages showed consistent gold-positive staining on their cell surface. In contrast, other dermal cells, including fibroblasts, lymphocytes, and mast cells, as well as dermal fibers, were not decorated with gold; dermal Langerhans cell-like dendritic cells (LC/DC), though they did show gold labeling in some intracytoplasmic organelles, did not show any gold particles along their plasma membranes. Therefore, although macrophages in normal human dermis exhibit variability with regard to their localization and shape, they regularly and constitutively expressed CD36. CD36 molecules may be considered a useful marker for macrophages in normal human dermis and may furthermore confer on macrophages, or a subpopulation thereof, intriguing functional properties (e.g., downregulatory capacity versus upregulatory capacity subserved by LC/DC) within the cutaneous immune system.

Antibodies, Monoclonal↗
PubMed1996

Evidence for atrophy and apoptosis in the prostates of men given finasteride.

Finasteride, a 5 alpha-reductase inhibitor, decreases prostate size and improves symptoms in men with benign prostatic hyperplasia. However, little is known about prostate histopathology in men taking finasteride. To determine the mechanism by which finasteride reduces prostate size, tissue was collected at the time of prostatectomy from men taking either no medication (n = 10) or 5 mg finasteride daily for 6-18 days (n = 6; group 1), 23-73 days (n = 5; group 2), or 3 months to 4 yr (n = 5; group 3). To assess whether finasteride causes epithelial atrophy, morphometric measurement of epithelial cell and duct width was used. The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (tTG), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. Anti-tTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. The staining for DNA breaks and the tTG staining also indicate that an increased rate of apoptosis is occurring transiently in these prostates. We conclude that finasteride causes prostate involution through a combination of atrophy and cell death.

5-alpha Reductase Inhibitors↗
PubMed1995

Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Inhibition of human B-cell chronic lymphocytic leukemia by a monoclonal antibody in xenograft models.

To establish xenograft models of human B-cell chronic lymphocytic leukemia (CLL), we inoculated 5 x 10(6) D10-1 cells, a subline of Epstein-Barr virus (EBV)-transformed human B-cell CLL with a marker chromosomal anomaly, into SCID or irradiated nude mice by the intravenous (i.v.) or intraperitoneal (i.p.) route. All i.p. tumor-inoculated mice developed rapidly progressive, lethal ascites tumor, and 100% of i.v. tumor-inoculated mice developed disseminated CLL. All mice died of tumor within 8 weeks of tumor inoculation. Tumor-inoculated SCID mice died earlier with wider tumor dissemination than the tumor-inoculated nude mice. All the tumor-inoculated mice had histologically confirmed metastases in lymph nodes, and most of them also had metastases in one or more internal organs. Cytogenetic analysis confirmed the origin of these tumors from the xenografted D10-1 cells. The D10-1 cells harvested from the xenografts did not differ from the parent D10-1 cells as regards (i) reactivity with 2 monoclonal antibodies (MAbs) directed against CLL-associated cell-surface antigens; (ii) rate of proliferation in vitro; and (iii) sensitivity to the 2 chemotherapeutic agents, methotrexate and adriamycin. Administration of 50 micrograms/mouse of Dal B02, an IgG1 (kappa) MAb directed against surface-associated antigens of human B-cell CLL, significantly prolonged the survival of D10-1-inoculated nude and SCID mice. The MAb was more effective in D10-1-inoculated nude mice than in SCID mice. In all the D10-1 xenograft models, the effectiveness of Dal B02 decreased with higher tumor load but increased with the amount of MAb injected. Dal B02 F(ab)'2 fragment failed to demonstrate any anti-tumor activity in D10-1-inoculated nude mice. In vitro assays revealed that Dal B02 had no direct inhibitory effect on D10-1 cells, but could be cytotoxic towards D10-1 cells in the presence of splenic cells or peritoneal macrophages from nude and SCID mice, or together with rabbit complement.

Animals↗