A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.

This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class II(hi), and express OX62, CD11c, and B7. CD4(+)/OX41(+) DCs are strong antigen-presenting cells (APCs). CD4(-)/OX41(-) DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell-restricted cytokeratins, and nonspecific esterase (NSE)(+) inclusions, not seen in OX41(+) DCs. Identical patterns of NSE electrophoretic variants exist in CD4(-)/OX41(-) DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE(+) DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE(+) DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

Monoclonal IgM antibodies that inhibit primary Moloney murine sarcoma growth.

Monoclonal IgM antibodies with specificity for Moloney murine sarcoma virus (M-MuSV)-Moloney murine leukemia virus (M-MuLV) from two hybridoma clones have been isolated and characterized. The monoclonal antibodies have specificity for a cytoplasmic and cell surface Friend-Moloney-Rauscher group-specific antigen. Immunoelectron microscopy revealed antibody binding to the surface of virus-expressing cells but not to the budding virus particles. Treatment of M-MuSV-injected mice with monoclonal IgM anti-M-MuSV significantly inhibited tumor growth compared to virus-inoculated animals receiving either saline or MOPC 104E. Nude mice exhibited delayed tumor induction following treatment with the monoclonal antibodies but ultimately died from tumor growth. Virus-injected euthymic mice that were treated with monoclonal IgM anti-M-MuSV generated a potentiated spleen cell-mediated cytotoxicity against Moloney sarcoma cells compared to virus-infected treated with saline. This potentiation of cytotoxicity remained after trypsinization of the spleen cells and thus was probably not due to passively adsorbed monoclonal antibody. The antibodies alone or in the presence of complement did not neutralize M-MuLV. The IgM antibodies induced specific tumor cell cytotoxicity in vitro mediated by complement spleen cells, lymph node cells, or thymus cells. In conclusion, two monoclonal IgM anti-M-MuSV antibodies that bind to the tumor cell surface did not neutralize virus can inhibit primary M-MuSV-induced tumor growth in vivo. The regression event appeared to involve heterogeneous mechanisms. Complete regression remained thymus dependent even with passive antibody therapy, but significant tumor growth inhibition was produced independent of T-cells. In vitro these IgM antibodies induced complement and cell-mediated cytotoxicity.

SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.

SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.

Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide.

Many reports have cited coexpression of platelet-derived growth factor (PDGF) and its receptors by tumor cells or cells supporting tumor growth, suggesting both autocrine and paracrine mechanisms for PDGF-mediated tumor growth. We found that a small organic molecule, N-[4-(trifluoromethyl)phenyl] 5-methylisoxazole-4-carboxamide (SU101, leflunomide), inhibited PDGF-mediated signaling events, including receptor tyrosine phosphorylation, DNA synthesis, cell cycle progression, and cell proliferation. SU101 inhibited PDGF-stimulated tyrosine phosphorylation of PDGF receptor (PDGFR) beta in C6 (rat glioma) and NIH3T3 cells engineered to overexpress human PDGFRbeta (3T3-PDGFRbeta). SU101 blocked both PDGF- and epidermal growth factor (EGF)-stimulated DNA synthesis. Previously, this compound was shown to inhibit pyrimidine biosynthesis by interfering with the enzymatic activity of dihydroorotate dehydrogenase. In the current study, EGF-stimulated DNA synthesis was restored by the addition of saturating quantities of uridine, whereas PDGF-induced DNA synthesis was not, suggesting that the compound demonstrated some selectivity for the PDGFR pathway that was independent of pyrimidine biosynthesis. Selectivity was further demonstrated by the ability of the compound to block the entry of PDGF-stimulated cells into the S phase of the cell cycle, without affecting cell cycle progression of EGF-stimulated cells. In cell growth assays, SU101 selectively inhibited the growth of PDGFRbeta-expressing cell lines more efficiently than it inhibited the growth of PDGFRbeta-negative cell lines. SU101 inhibited the s.c., i.p., and intracerebral growth of a panel of cell lines including cells from glioma, ovarian, and prostate origin. In contrast, SU101 failed to inhibit the in vitro or s.c. growth of A431 and KB tumor cells, both of which express EGF receptor but not PDGFRbeta. SU101 also inhibited the growth of D1B and L1210 (murine leukemia) cells in syngeneic immunocompetent mice, without causing adverse effects on the immune response of the animals. In an i.p. model of tumor growth in syngeneic immunocompetent mice, SU101 prevented tumor growth and induced long-term survivors in animals implanted with 7TD1 (murine B-cell hybridoma) tumor cells. Because PDGFRbeta was detected on most of the tumor cell lines in which in vivo growth was inhibited by SU101, these data suggest that SU101 is an effective inhibitor of PDGF-driven tumor growth in vivo.

Moloney leukemia virus-induced cell surface antigen mimicry by monoclonal antibodies.

We have investigated antigen-independent modulation of immune responses by monoclonal antibodies directed against both viral and nonviral antigens. BALB/c mice were immunized with monoclonal IgM (i.e. Ab1) specific for either Moloney murine leukemia virus-induced cell surface antigen (MCSA) or the hapten 2,4-dinitrophenyl (DNP). Injection with either Ab1 activated a functional idiotypic (Id) network as evidenced by production of both anti-Id (Ab2) antibodies and anti-anti-Id (Ab3) antibodies. A subset of induced Ab3 (designated Ab1'), exhibited specificity for antigen (virus or DNP). In mice immunized with anti-Id antibodies (Ab2), production of Ab3 and Ab1' was also observed. In the MCSA system, antibody-induced Ab1' responses were effective in protecting mice from tumor development upon subsequent challenge with live virus. Furthermore, antigen-independent modulation of immunity to both viral and nonviral antigens was found to be thymus-dependent. Similar findings in other viral systems suggest that antibody-induced activation of Id networks may prove a viable alternative vaccine strategy that can elicit antigen-specific responses, and in some cases protection, in the apparent absence of exposure to antigen.

Isotype distribution and specificity of the antibody response to primary Moloney murine sarcoma virus infection in BALB/c mice.

The development and isotype distribution of Moloney murine leukemia virus (M-MuLV)-specific serum antibodies following primary inoculation with Moloney murine sarcoma/leukemia virus (M-MuSV/M-MuLV) in adult BALB/c mice have been investigated using an enzyme-linked immunosorbent assay (ELISA). The primary antibody responses to M-MuSV/M-MuLV consisted of the IgM, IgG2a, IgG2b, and IgG3 isotypes; no M-MuLV-specific serum IgG1 or IgA antibodies were detected. The detectable antibody response was biphasic, with an early peak of virus-specific titers seen between 10 and 15 days after inoculation and a second peak seen in regressor sera. Pooled regressor sera contained IgM, IgG2a, and IgG2b antibodies which bound to M-MuLV-expressing lymphoma cells. Immunoelectron microscopy with regressor sera showed IgG bound both to infected cell surfaces and to mature viral particles, while IgM bound only to infected cell surfaces. These findings were supported by immunoprecipitation analyses which demonstrated binding of the M-MuLV-specific antibodies to both virion-associated and cell-associated antigens encoded by the gag and env genes.

Ontogeny of tolerogen-responsive lymphocytes following neonatal inoculation of class II disparate semiallogeneic cells.

Spleens of adult mice of the A strain background that were rendered tolerant as neonates of class II alloantigens only (A.TH tolerant of A.TL, A.TL tolerant of A.TH) contain large numbers of tolerogen-responsive T cells, many of which secrete IL-4, but not IL-2. Since these spleens also contain suppressor cells that can adoptively transfer skin allograft acceptance in vivo and can prevent generation of class II-specific cytotoxic T cells in vitro, it is important to determine the origins during postnatal development of these cells. Class II disparate, semiallogeneic haematopoietic cells were injected into newborn A.TH and A.TL mice. Periodically thereafter (1 to 60 days post-injection, but prior to challenge with a tolerogen-bearing skin graft), thymocytes and splenocytes from these mice were examined in vitro for tolerogen-specific reactivity in mixed lymphocyte reactions during which proliferation and IL-2 and IL-4 production were assayed. Within 24 hours of neonatal injection, the thymus and spleens of injected mice were profoundly depleted of tolerogen-responsive T cells. However, there was no commensurate loss of I-E-related V beta 5+ cells in the thymus of A.TH mice that received neonatal inoculations of I-E-bearing A.TL cells. During the ensuing weeks, tolerogen-responsive proliferative and IL-4-secreting T cells were detected in thymus and spleen. However, not until after the mice were more than 60 days of age were tolerogen-responsive cells able to secrete IL-2. Since physical clonal deletion of tolerogen-related V beta 5+ cells is a characteristic of neither neonatal nor adult A.TH and A.TL mice that received injections of semiallogeneic cells at birth, and since tolerogen-responsive IL-4 producing cells exist in adult mice that have permanently accepted (A.TH x A.TL)F1 skin grafts, our results imply that the tolerogen-responsive T cells detected in adult tolerant mice are descendants of the novel IL-4-producing T cells that arise in the thymus almost immediately after the tolerance conferring inoculum of semiallogeneic cells. The possible mechanisms responsible for generation of IL-4-producing, tolerogen-responsive T cells and the role of these cells in maintenance of tolerance of class II alloantigens are discussed.

Psychiatrists' referrals to self-help groups for people with mood disorders.

The study examined psychiatrists' referrals to and support for participation in self-help groups by people with mood disorders. Massachusetts and Michigan psychiatrists with a special interest in patients with mood disorders were surveyed; the 278 respondents represented a 78 percent response rate. About three-fourths of the psychiatrists reported that they made referrals to and felt knowledgeable about self-help groups. However, less than half had self-help literature available or discussed self-help groups with their patients. Beliefs that a patient would gain a better understanding of the illness and would receive support after an episode of illness were positively related to support for self-help. Beliefs that the program was inappropriate and that it lacked professional oversight were negatively related.

Attitudes of AA contact persons toward group participation by persons with a mental illness.

Alcoholics Anonymous groups are underused by persons with the dual diagnoses of mental illness and substance use disorder, and mental health professionals are cautious about referring them to AA because of fears that the AA group will discourage them from taking prescribed medication. The study assessed the attitudes of 125 AA contact persons about the participation of persons with mental illness. The majority had positive attitudes toward such persons, and 93 percent indicated that they should continue taking their medication. Fifty-four percent felt that participation in a group especially for persons with a dual diagnosis would be more desirable than in a traditional AA group. However, such groups are often not available.

A follow-up study of patients hospitalized after minor head injury.

Minor head injury accounts for 95% of all head injury. In this study 62 patients, hospitalized after minor head injury, were assessed within 48 h, and invited to attend for review and retesting 3 months later. Thirty-five patients were followed up in this way and 11 more were interviewed over the telephone. There was significant improvement on all psychometric tests between initial evaluation and follow-up. Between 51% and 86% reported troublesome late post-concussional symptoms, of which headaches and tiredness were the most frequently reported symptoms. Length of post-traumatic amnesia (PTA) was related to severity of symptoms. Clinical levels of anxiety and stress were noted in approximately one-third of the whole group; 95% of the group had returned to work by 3 months with a mean absence rate of 9.4 days. The therapeutic implications of these results are discussed.

The use of self-help groups as supportive reference communities.

Self-help groups such as Recovery Inc., Parents without Partners, and Alcoholics Anonymous have a unique role in relation to the professional system of human services. From the professional's standpoint, such groups may be viewed as self-sufficient programs, concurrent treatment programs, and as sources of information and users of consultation. Patterns of influence operative in self-help groups are examined, and suggestions made for professional cooperation with such groups to the greater benefit of clients.

Predictors of psychosocial outcomes for patients with mood disorders: the effects of self-help group participation.

This study examined the predictors of psychosocial outcomes (daily functioning and management of illness) for people with mood disorders. After controlling for demographic, severity of illness, and social support predictor variables, the study evaluated whether participation in self-help groups would predict improved psychosocial outcomes. Post-hospitalization data were examined for 144 mood disorder patients using hierarchic multiple regression. More education predicted improved daily functioning; self-help involvement and education predicted management of illness. The implications of these findings for providing recovery-oriented rehabilitation services are discussed.

Interpreting Parents Anonymous as a source of help for those with child abuse problems.

A study of reasons for joining the self-help group offers some considerations and guidelines for child welfare workers recommending this step to clients.