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Biomedical subjects

T Utsugi

Publications and source records attributed to T Utsugi.

At least 55 records · Page 3Linked to original sources
PubMed1996

Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer.

We synthesized a potent new antitumor podophyllotoxin derivative (4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung metastatic cancer. TOP-53 exhibited twice the inhibitory activity of etoposide (VP-16) against topoisomerase II and induced DNA strand breaks but showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 microg/ml and 0.26-8.9 microg/ml against marine tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted significant efficacy equivalent to that of VP-16 on s.c.-implanted murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5 times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active for two of five tumors. Potent inhibitory activity of TOP-53 was also found against a lung tumor (Lewis lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lung cancers but also strongly active against lung localized tumor and metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to its high distribution into the lung and its persistence. TOP-53 is expected to be highly effective against lung cancer including NSCLC and various lung metastatic tumors in the clinical field.

Animals↗
PubMed1996

A new type of CD4+ suppressor T cell completely prevents spontaneous autoimmune diabetes and recurrent diabetes in syngeneic islet-transplanted NOD mice.

Insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse results from effector T cell-mediated autoimmune processes directed against pancreatic beta cells. These effector T cell-mediated beta cell-specific autoimmune processes can be blocked by transfusion with supressor T cells. The CD4+ autoreactive T cell clone, NY4.2, isolated from lymphocytes infiltrating the pancreatic islets of NOD mice was transfused into young NOD mice and none of the animals became diabetic. Similarly, when NY4.2 cells were transfused into acutely diabetic NOD mice prior to syngeneic islet transplantation, the grafted islets were not destroyed and the animals maintained normoglycaemia. This investigation was initiated to determine how our cloned CD4+ autoreactive suppressor T cells are able to inhibit effector T cell-mediated beta cell destruction in NOD mice. We found that NY4.2 cells, which responded to self MHC class II determinants, had a significant immunosuppressive effect on proliferative responses of splenic effector T cells from NOD mice. This suppressive activity of the NY4.2 cells was a result of soluble factors secreted by them. The clone was found to produce substantial amounts of transforming growth factor beta (TGF-beta), IL-10, and IFN-gamma, but not IL-2 or IL-4, indicating that this T cell clone is not a member of either the classic Th1 or Th2 cell type. The suppressive activity of NY4.2 cells was abrogated by treatment with anti-TGF-beta antibodies, but not by treatment with anti-IL-10 or anti-IFN-gamma antibodies. On the basis of these observations, we suggest that a new type of CD4+ suppressor T cell, NY4.2, by secreting TGF-beta, can prevent effector T cell-mediated beta cell destruction.

Animals↗
PubMed1996

Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8+ T-cell clones in vivo.

NOD mouse-derived beta-cell-specific cytotoxic T-cell (beta-CTL) clones are diabetogenic in adult NOD mice, but only if co-injected with splenic CD4+ T-cells from diabetic animals. This investigation was initiated to determine whether infiltration of pancreatic islets by beta-CTL is a major histocompatibility complex (MHC) class I-restricted response, and whether beta-CTL has a direct cytopathic effect on beta-cells in vivo. Pancreatic islets from BALB/c (H-2d) or B6 (H-2b) mice were transplanted under the renal capsule of streptozotocin (STZ)-induced diabetic (NOD x BALB/c) F1 (H-2Kd, H-2Dd,b) or NOD x B6) F1 (H-2Kd,b, H-2Db) mice, respectively. H-2Kd-restricted beta-CTL clones from NOD mice were transfused into euglycemic mice within 3 days after transplantation. In all of the H-2d islet-grafted (NOD x BALB/c) F1 mice that received the beta-CTL clones, the beta-CTLs homed into the grafts, recruited host Mac-1+ cells and CD4+ and CD8+ T-cells, and caused diabetes within 7 days. In contrast, none of the H-2b islet-grafted (NOD x B6) F1 mice who received the beta-CTL clones and none of the H-2d islet-grafted (NOD x BALB/c) F1 mice who received a non-beta-cell cytotoxic CTL clone (N beta-CTL) developed graft inflammation or diabetes. Depletion of CD4+ T-cells in H-2d islet-grafted (NOD x BALB/c) F1 mice did not prevent beta-CTL clone-induced diabetes but reduced its severity. In contrast, when the beta-CTL clones were injected > 8 days after transplantation, none of the H-2d islet-grafted (NOD x BALB/c) F1 mice became diabetic or developed graft inflammation. We conclude that (1) islet-derived beta-CTLs can destroy beta-cells in vivo; (2) infiltration of grafted islets by beta-CTLs is an MHC class I-restricted response; (3) beta-CTLs can recruit naive CD4+ T-cells to the site, leading to further beta-cell damage; and (4) revascularized islet grafts are, like pancreatic islets of irradiated adult NOD mice, "sequestered" from circulating beta-CTLs.

Animals↗
PubMed1996

Age-related alteration of pancreatic beta-cell function. Increased proinsulin and proinsulin-to-insulin molar ratio in elderly, but not in obese, subjects without glucose intolerance.

OBJECTIVE: To determine the secretion of insulin, C-peptide, and proinsulin after oral glucose loading in healthy elderly subjects compared with middle-aged subjects with and without obesity and with NIDDM. RESEARCH DESIGN AND METHODS: Subjects fell into four groups: nonobese middle-aged normal control subjects (CNT group; n = 38, 40-64 years old); obese normal subjects (OB group; n = 18, 40-64 years old); nonobese NIDDM subjects (NIDDM group; n = 28, 40-64 years old); and nonobese elderly subjects (OL group; n = 17, 65-92 years old). Insulin, C-peptide, and proinsulin were determined by radioimmunoassay in plasma samples taken at 0, 30, 60, and 120 min during a 75-g oral glucose tolerance test (OGTT). RESULTS: There were no differences in plasma glucose during the OGTT among the three nondiabetic groups. Hyperinsulinemia was significant in the OB and NIDDM groups but not in the OL group. On the other hand, absolute hyperproinsulinemia was significant in the OL and NIDDM groups compared with the CNT group. Increased proinsulin was rather dominant in the OL group, especially late after glucose loading. Molar ratios of proinsulin to insulin or C-peptide thus were significantly higher in the OL and NIDDM groups. CONCLUSIONS: Alteration of pancreatic beta-cell function independent of that seen with NIDDM occurred in relation to aging. This may be a predisposing factor to the development of impaired glucose tolerance or NIDDM in elderly subjects, that is, independent of obesity.

Adult↗
PubMed1995

A high dose of the STM1 gene suppresses the temperature sensitivity of the tom1 and htr1 mutants in Saccharomyces cerevisiae.

A new gene (STM1; suppressor of tom1) of Saccharomyces cerevisiae was isolated by the ability to suppress the temperature sensitivity of a tom1 mutant, by increasing its gene dosage. The gene could also suppress the temperature sensitivity of the htr1 disruptant (Kikuchi et al. (1994) Mol. Gen. Genet. 245, 107-116) and was physically mapped in the region near PEP3 on chromosome XII R. The predicted gene product (29,999 Da) is basic and partially homologous to various histone H1. The level of the gene expression increased 2-fold when exposed to mating pheromone.

Amino Acid Sequence↗
PubMed1995

Beta-cell-cytotoxic CD8+ T cells from nonobese diabetic mice use highly homologous T cell receptor alpha-chain CDR3 sequences.

Insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a cell-mediated autoimmune process against pancreatic beta-cells. We have shown that beta-cell-cytotoxic CD8+ T cell clones can transfer IDDM to irradiated NOD mice if co-injected with nondiabetogenic CD4+ spleen T cells. To determine whether CTLs recruited to pancreatic islets recognize a restricted set of local Ags, we sequenced TCR-alpha and TCR-beta cDNA generated by anchor PCR from CD8+ CTL lines and clones derived from islets of 10 different NOD mice. These CTL lines were oligoclonal, but did not show skewed V alpha, V beta, J alpha, or J beta gene usage when compared with CD8+ spleen T cells. However, of the 26 different CTL-derived TCR-alpha sequences from all of these CTL lines and clones, 17 (65%) used one of three highly related, N region-encoded, CDR3 motifs. Motifs 1 and 2 (7 clonotypes each) contained a hydrophobic amino acid followed by Arg and a negatively charged or a polar residue (Asn or Gly), respectively. Motif 3 (3 clonotypes) was x-Arg-Gly. In 12 of these 17 rearrangements, the core sequence was followed by Tyr or Ser. By contrast, none of 31 different TCR-alpha rearrangements used by CD8+ spleen T cells encoded motifs 1 or 2, and only one encoded motif 3. Different TCR-beta rearrangements within individual lines also used homologous CDR3 sequences, but these sequences varied between lines. Skewed TCR-alpha-CDR3 usage by islet-derived CTLs was substantiated further by isolation of CTL clones transcribing highly homologous TCR-alpha, but different TCR-beta, rearrangements. These data suggest that CTLs recruited to pancreatic islets during spontaneous IDDM recognize a restricted set of beta-cell autoantigenic determinants.

Amino Acid Sequence↗
PubMed1994

Prevention of recurrent diabetes in syngenic islet-transplanted NOD mice by transfusion of autoreactive T lymphocytes.

Islet transplantation has been considered to be one of the best methods for the cure of type I diabetes, but transplanted islets are eventually destroyed by the host's cell-mediated autoimmune responses unless immunosuppressive agents are given. This investigation was initiated to develop a method for the prevention of beta cell destruction in transplanted islets without the use of immunosuppressive drugs. We have recently cloned CD4+ autoreactive T cells (NY1.1 and NY4.2) from lymphocytes infiltrating the pancreatic islets of nonobese diabetic (NOD*) mice and have shown that these cells respond to self MHC class II determinants. When the T cell clones (10(7) cells of either NY1.1 or NY4.2) were transfused into acutely diabetic NOD mice 2 to 3 days before transplantation of syngenic islets (400) into the subrenal space, the transplanted islets were not destroyed, and the animals maintained normoglycemia over 100 days without insulin treatment. In contrast, NOD mice that received syngenic islets (400) without the transfusion of an autoreactive T cell clone showed a recurrence of diabetes and massive mononuclear cell infiltration of the grafted islets within 17 days. On the basis of these observations, it is concluded that CD4+ autoreactive T lymphocytes can prevent the recurrence of insulitis and development of diabetes in pancreatic islet-transplanted NOD mice, without treatment with immunosuppressive drugs.

Animals↗
PubMed1994

Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice.

CD8+ islet cell-specific CTL lines and clones were established from lymphocytes infiltrating the pancreatic islets of acutely diabetic nonobese diabetic (NOD) mice from two subcolonies (NOD/Yn and NOD/Lt). CTL from NOD/Yn mice were predominantly cytotoxic against H-2b+ islet cells and to a lesser extent against H-2d+ islet cells. On the other hand, CTL from NOD/Lt mice were cytotoxic against H-2d+ but not against H-2b+ islet cells. Three of four CTL clones derived from NOD/Yn mice were H-2Db restricted, whereas two of two CTL clones derived from NOD/Lt mice were H-2Kd restricted. However, all of the H-2Kd restricted T cell clones expressed the same TCR, regardless of the NOD subcolony from which they were derived, compatible with a restricted repertoire. When two representative CTL clones were transferred into irradiated young NOD mice, neither induced insulitis or diabetes. However, transfer of these clones, together with CD4(+)-rich NOD splenocytes depleted of CD8+ T cells, caused severe insulitis and diabetes. When recipient NOD mice were treated with anti-CD4 mAbs, none of the mice developed insulitis or diabetes. Most of the irradiated NOD mice that received CD8-depleted splenocytes alone did not become diabetic. Through these studies we show that CTL clones can destroy pancreatic beta-cells as final effectors but that these clones require signals from CD4+ T cells to effect beta-cell damage.

Amino Acid Sequence↗
PubMed1994

The role of insulin in coronary atherosclerosis.

In 197 patients with coronary artery disease (CAD) who underwent coronary angiography, 75 g oral glucose tolerance test (OGTT) was performed, measuring plasma glucose(PG) and plasma insulin (IRI) at 4 time points (0, 30, 60 and 120 min). Subjects were separated into two groups by their insulinogenic index (I.I. = delta IRI/delta PG from 0 up to 30 min), 99 cases with good insulin response (I.I. > or = 0.4) and 98 cases with poor insulin response (I.I. < 0.4). Only two subjects were diabetic in good insulin response, while 37 were diabetic in poor insulin response. The severity of coronary atherosclerosis was expressed as a coronary index (CI), calculated according to Balcon's method. Fasting PG and the sum of PG were significantly higher in the latter group, while the sum of IRI was significantly lower. CI was not significantly different, however. In the group with good insulin response, the severity of CAD was significantly correlated to fasting IRI (n = 99, r = -0.387, P < 0.02), but, there was no such relationship in the other group. We conclude that hyperinsulinemia might be a risk factor for ischemic heart disease, but in diabetics it is difficult to link the relationship between fasting IRI and CI.

Adult↗
PubMed1993

Prevention of autoimmune type I diabetes by CD4+ suppressor T cells in superantigen-treated non-obese diabetic mice.

The development of autoimmune type I diabetes in the NOD mouse appears to be controlled by both genetic and environmental factors. This investigation was initiated to determine whether exogenous superantigens, as environmental factors, can influence the development of diabetes. Several staphylococcal enterotoxins (SE) (SEA, SEC1, SEC2, or SEC3), which are known superantigens, were injected i.v. into female NOD mice at 4 and 10 wk of age. At 32 wk of age, the incidence of diabetes in the SE-treated mice ranged from 6 to 12.5%; this was significantly lower than that of mice treated with PBS--64%. There was no significant difference in effectiveness among the various SE used. SE induced a modest decrease in T lymphocytes bearing specific V beta TCR 2 wk after injection, but this effect did not persist past 4 wk. To elucidate the mechanism of the SE effect, suppressor activity in SE-treated mice was evaluated. Splenocytes from SE-treated mice inhibited the transfer of diabetes by splenocytes from acutely diabetic NOD mice when injected into irradiated young NOD mice; only 10% became diabetic. In contrast, 83% of the mice receiving splenocytes from PBS-treated control mice became diabetic. Suppressor activity of splenocytes from SE-treated mice was diminished by the depletion of CD4+ T cells, but not by the depletion of CD8+ T cells, indicating that the suppressor cells belonged to the CD4+ T class of lymphocytes. On the basis of these observations, we conclude that exogenous superantigens activate CD4+ suppressor T cells, leading to the prevention of autoimmune type I diabetes in NOD mice.

Animals↗
PubMed1992

Immunotherapy of murine renal adenocarcinoma by systemic administration of liposomes containing the synthetic macrophage activator CGP 31362 or CGP 19835A in combination with interleukin 2 or gamma-interferon.

The purpose of these experiments was to evaluate the possibility that the systemic administration of liposomes containing synthetic macrophage activation CGP 31362 or CGP 19835 in mice which were simultaneously receiving injections of gamma-interferon or interleukin 2 would lead to enhanced regression of spontaneous lung metastases produced by syngeneic renal adenocarcinoma. The kidneys of BALB/c mice were given injections of renal adenocarcinoma cells, and 10 days later the kidney with local tumor was surgically resected. These mice were then given injections i.v. with liposomes and with gamma-interferon (s.c.) or interleukin 2 (i.p.). Systemic administration of MLV-CGP 31362 and MLV-CGP 19835A significantly reduced the number of lung metastases in nephrectomized mice. Both lung tumor burden and regional recurrence were further reduced by the s.c. injection of gamma-interferon or i.p. injection of interleukin 2. Long-term survivors were observed only in the groups of animals treated with liposomes containing macrophage activators and with lymphokines. Evaluation of host responsiveness to this immunotherapy revealed in situ activation of alveolar macrophages by administration of MLV-CGP 31362 or MLV-CGP 19835A, which was enhanced in mice also treated with interleukin 2. Normal levels of natural killer cell activity were reduced in the spleens of tumor-bearing mice but were restored subsequent to treatment with MLV-CGP 31362. These results indicate the potential usefulness of treating metastatic renal cell carcinoma by systemic administration of liposomes containing synthetic macrophage activators in combination with parental injections of lymphokines.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Isolation and characterization of cDNA clones encoding cdc2 homologues from Oryza sativa: a functional homologue and cognate variants.

Using probes obtained by PCR amplification, we have isolated two cognate rice cDNAs (cdc2Os-1 and cdc2Os-2) encoding structural homologues of the cdc2+/CDC28 (cdc2) protein kinase from a cDNA library prepared from cultured rice cells. Comparison of the deduced amino acid sequences of cdc2Os-1 and cdc2Os-2 showed that they are 83% identical. They are 62% identical to CDC28 of Saccharomyces cerevisiae and much more similar to the yeast and mammalian p34cdc2 kinases than to rice R2, a cdc2-related kinase isolated previously by screening the same rice cDNA library with a different oligonucleotide probe. Southern blot analysis indicated that the three rice clones (cdc2Os-1, cdc2Os-2 and R2) are derived from distinct genes and are each found in a single copy per rice haploid genome. RNA blot analysis revealed that these genes are expressed in proliferating rice cells and in young rice seedlings. cdc2Os-1 could complement a temperature-sensitive yeast mutant of cdc28. However, despite the similarity in structure, both cdc2Os-2 and R2 were unable to complement the same mutant. Thus, the present results demonstrate the presence of structurally related, but functionally distinct cognates of the cdc2 cell cycle kinase in rice.

Amino Acid Sequence↗
PubMed1992

Frozen-thawed human blood monocytes respond reproducibly to activation stimuli: implications for screening of BRMs.

The purpose of this study was to identify the optimal freezing conditions for human blood monocytes to allow their recovery and use for in vitro screening of activation stimuli. Human monocytes separated from buffy coats of healthy blood donors were suspended at a density of 1 x 10(7) cells/ml in freezing medium consisting of 70% medium: 20% fetal bovine serum: 10% DMSO frozen in a stepdown freezer, and stored at -180 degrees C. Monocytes were thawed at different times up to 4 months later. Viability was > 90%. Fresh monocytes from different donors and frozen monocytes thawed at different times were incubated with different concentrations of lipopolysaccharide, muramyl tripeptide, muramyl dipeptide, or lipopeptide. Tumoricidal activity and IL-1 production of fresh monocytes varied greatly among the 5 different preparations. In contrast, the frozen monocytes (thawed at different times) produced uniform levels of antitumor activity and IL-1 production. These results show that monocytes recovered from frozen storage maintain their ability to respond to activation stimuli in a uniform and reproducible manner. Thus, the use of frozen-thawed monocytes is recommended for screening of macrophage-activating agents.

Cryopreservation↗
PubMed1992

[Tsutsugamushi disease found in Haruna District, Gunma Prefecture--evaluations of the clinical features and the outbreak pattern].

From November to December in 1990, 7 cases of tsutsugamushi disease were found first in the southern foot of Mt. Haruna of Gunma Pref., Japan. The present study was conducted to clarify the clinical features and the outbreak pattern of rickettsial infection in this area. All the patients consisting of 6 males and 1 female farmers were admitted to our hospital, complaining of high fever, chills and skin rash on 5-12 days after working in the field. Based on laboratory examinations and one (or two) typical eschar, a tentative diagnosis of tsutsugamushi disease was made and all patients became better soon after the therapy with intravenous administration of minocyclin (200 mg/day). The high titer of serum antibody to Karp type Rickettsia (Orientia?) tsustugamushi was detected by an immunoperoxidase test (IP) in most of the patients, and also a Karp-like strain was isolated from only one patient, probably due to low virulence to mice. The agricultural areas along the Agatuma and Nakuta rivers in the northern foot of Mt. Haruna have been well known as the most endemic foci of the disease in Gunma Pref. Nevertheless, it was suggested that outbreaks of the disease might be potentially wide-spread throughout this Pref., when the prevalences of the disease were evaluated as incidences to a hundred thousand inhabitants or adjusted by the density of agricultural populations of each administrative divisions. As most of the patients in Gunma Pref. have been officially reported in autumn, a statistical trial indicates that there is a significant correlation between the levels of temperature and outbreaks of the disease in autumn.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

A new animal model of non-insulin-dependent diabetes mellitus induced by the NDK25 variant of encephalomyocarditis virus.

Intraperitoneal inoculation with NDK25, a variant of Encephalomyocarditis (EMC) virus which has been newly cloned from the M variant of EMC virus (EMC-M), caused DBA/2 mice to develop noninsulin-dependent diabetes mellitus. The NDK25-infected mice demonstrated abnormal glucose tolerance from 1 to 3 weeks after inoculation. The infection resulted in mild insulitis and the destruction of pancreatic beta cells at 1 week after inoculation and led to a significant reduction in the insulin content of the pancreas, but there was no ketonuria. The insulin content of the pancreas was recovered considerably from 15 +/- 3 at 1 week to 95 +/- 16 micrograms/g pancreas at 12 weeks, although the latter value was still significantly lower than that of the control mice (P < 0.05). Under microscopy, mild and partial infiltration of mononuclear cells was observed in about half the pancreatic islets only 1 week after inoculation, and then disappeared. Thus, we believe we have established a new model of noninsulin-dependent diabetes mellitus using the NDK25 variant of EMC virus.

Animals↗
PubMed1991

Therapy of spontaneous lung metastasis of murine renal adenocarcinoma by systemic administration of liposomes containing the macrophage activator CGP 31362.

Current therapies for renal cell carcinoma have been limited by the unresponsiveness of metastatic disease to conventional treatments. Although the use of biological response modifiers as adjuvant therapy has generally not been successful against disseminated disease, in situ activation of macrophages to a tumoricidal state by liposome-encapsulated immunomodulators has been shown to eradicate metastatic cancer in murine tumor models. We, therefore, designed experiments to evaluate the ability of a new macrophage activator, CGP 31362, a synthetic bacterial cell wall analogue, to cause regression of spontaneous lung metastases in mice whose primary renal adenocarcinoma was removed by nephrectomy. Delivery of the CGP 31362 to the lungs was accomplished by its encapsulation in multilamellar phospholipid liposomes (MLV-CGP 31362). Therapy with repeated i.v. injections of MLV-CGP 31362 significantly reduced the number of lung metastases in nephrectomized mice. Therapeutic efficacy of MLV-CGP 31362 was influenced by the encapsulation ratio of CGP 31362 to total phospholipid, the dose of injected liposomes, and the frequency of administration. Optimal therapy was achieved by combining the use of i.v. MLV-CGP 31362 with the s.c. injection of recombinant murine gamma interferon. Administration of MLV-CGP 31362 prior to removal of the primary tumor and continuing postoperatively was superior to postoperative therapy alone. Several lines of evidence indicate that in situ activation of macrophages was responsible for the therapeutic effects of MLV-CGP 31362: (a) macrophages harvested from the lungs of treated mice had significant tumoricidal activity against cultured renal carcinoma cells, (b) activated macrophages, as defined by the MRP-14 marker, were present in lung tumor nodules of treated mice but not untreated mice, and (c) the in situ activation of alveolar macrophages was consistent with the in vivo deposition of 60% of radiolabeled MLV-CGP 31362 liposomes in the lungs following i.v. injection. The results reported here represent the first in vivo evaluation of MLV-CGP 31362 and offer additional evidence that macrophage combination with therapies that reduce tumor burden.

Adenocarcinoma↗
PubMed1991

Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes.

We determined whether the presence of phosphatidylserine (PS) in the outer membrane leaflet of human tumor cells correlated with their recognition by activated human monocytes. Three tumorigenic cell lines, A375 melanoma and A431 and Colo-16 carcinomas, and a normal human epidermal keratinocyte line (NHEK) were incubated with monocytes activated to the tumoricidal state by gamma-interferon and lipopolysaccharide. Activated human monocytes bound to and lysed all tumorigenic targets, while the nontumorigenic NHEK were neither bound nor killed. Semiquantitative analysis of PS in the outer leaflet of the cells revealed that the tumorigenic cells expressed 3-7-fold more PS than did the nontumorigenic NHEK. To determine whether enhanced PS expression on the tumor cells was responsible for their recognition by activated monocytes, NHEK were supplemented with exogenously supplied analogues of PS and phosphatidylcholine. PS-labeled NHEK but not phosphatidylcholine-labeled nor control NHEK bound to activated human monocytes. These results suggest a role for PS in monocyte recognition of tumor cells.

Carcinoma, Squamous Cell↗