Tumor cells expressing a retroviral envelope escape immune rejection in vivo

A model system for the in vivo control of tumor cell proliferation by the immune system has been used to assay for the possible immunosuppressive activity of retroviral proteins. Expression vectors for the entire or the transmembrane subunit of the Moloney murine leukemia virus envelope protein were constructed, as well as control vectors for irrelevant transmembrane proteins—or no protein. They were introduced either into MCA205 murine tumor cells, which do not proliferate upon s.c. injection into an allogeneic host, or into CL8.1 murine tumor cells, which overexpress class I antigens and are rejected in a syngeneic host. In both cases, expression of the complete envelope protein or of the transmembrane subunit resulted in tumor growth in vivo, with no effect of control vectors. Tumor cell growth results from inhibition of the host immune response, as the envelope-dependent effect was no more observed for MCA205 cells in syngeneic mice or for CL8.1 cells in x-irradiated mice. This inhibition is local because it is not observed at the level of control tumor cells injected contralaterally. These results suggest a noncanonical function of retroviral envelopes in the “penetrance” of viral infections, as well as a possible involvement of the envelope proteins of endogenous retroviruses in tumoral processes.

Immune response to a differentiation antigen induced by altered antigen: A study of tumor rejection and autoimmunity

Recognition of self is emerging as a theme for the immune recognition of human cancer. One question is whether the immune system can actively respond to normal tissue autoantigens expressed by cancer cells. A second but related question is whether immune recognition of tissue autoantigens can actually induce tumor rejection. To address these issues, a mouse model was developed to investigate immune responses to a melanocyte differentiation antigen, tyrosinase-related protein 1 (or gp75), which is the product of the brown locus. In mice, immunization with purified syngeneic gp75 or syngeneic cells expressing gp75 failed to elicit antibody or cytotoxic T-cell responses to gp75, even when different immune adjuvants and cytokines were included. However, immunization with altered sources of gp75 antigen, in the form of either syngeneic gp75 expressed in insect cells or human gp75, elicited autoantibodies to gp75. Immunized mice rejected metastatic melanomas and developed patchy depigmentation in their coats. These studies support a model of tolerance maintained to a melanocyte differentiation antigen where tolerance can be broken by presenting sources of altered antigen (e.g., homologous xenogeneic protein or protein expressed in insect cells). Immune responses induced with these sources of altered antigen reacted with various processed forms of native, syngeneic protein and could induce both tumor rejection and autoimmunity.

A wholly empirical explanation of perceived motion

Because the retinal activity generated by a moving object cannot specify which of an infinite number of possible physical displacements underlies the stimulus, its real-world cause is necessarily uncertain. How, then, do observers respond successfully to sequences of images whose provenance is ambiguous? Here we explore the hypothesis that the visual system solves this problem by a probabilistic strategy in which perceived motion is generated entirely according to the relative frequency of occurrence of the physical sources of the stimulus. The merits of this concept were tested by comparing the directions and speeds of moving lines reported by subjects to the values determined by the probability distribution of all the possible physical displacements underlying the stimulus. The velocities reported by observers in a variety of stimulus contexts can be accounted for in this way.

Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection.

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.

Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 microM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.

Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection.

The p40 subunit of interleukin 12 (IL-12p40) has been known to act as an IL-12 antagonist in vitro. We here describe the immunosuppressive effect of IL-12p40 in vivo. A murine myoblast cell line, C2C12, was transduced with retro-virus vectors carrying the lacZ gene as a marker and the IL-12p40 gene. IL-12p40 secreted from the transfectant inhibited the IL-12-induced interferon gamma (IFN-gamma) production by splenocytes in vitro. Survival of C2C12 transplanted into allogeneic recipients was substantially prolonged when transduced with IL-12p40. Cytokine (IL-2 and IFN-gamma) production and cytotoxic T lymphocyte induction against allogeneic C2C12 were impaired in the recipients transplanted with the IL-12p40 transfectant. Delayed-type hypersensitivity response against C2C12 was also diminished in the IL-12p40 recipients. Furthermore, serum antibodies against beta-galactosidase of the T-helper 1-dependent isotypes (IgG2 and IgG3) were decreased in the IL-12p40 recipients. These results indicate that locally produced IL-12p40 exerts a potent immunosuppressive effect on T-helper 1-mediated immune responses that lead to allograft rejection. Therefore, IL-12p40 gene transduction would be useful for preventing the rejection of allografts and genetically modified own cells that are transduced with potentially antigenic molecules in gene therapy.

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection.

During tumor progression, variants may arise that grow more vigorously. The fate of such variants depends upon the balance between aggressiveness of the variant and the strength of the host immunity. Although enhancing host immunity to cancer is a logical objective, eliminating host factors necessary for aggressive growth of the variant should also be considered. The present study illustrates this concept in the model of a spontaneously occurring, progressively growing variant of an ultraviolet light-induced tumor. The variant produces chemotactic factors that attract host leukocytes and is stimulated in vitro by defined growth factors that can be produced or induced by leukocytes. This study also shows that CD8+ T-cell immunity reduces the rate of tumor growth; however, the variant continues to grow and kills the host. Treatment with a monoclonal anti-granulocyte antibody that counteracts the infiltration of the tumor cell inoculum by non-T-cell leukocytes did not interfere with the CD8+ T-cell-mediated immune response but resulted in rejection of the tumor challenge, indicating a synergy between CD8+ T-cell-mediated immunity and the inhibition of paracrine stimulation.

Confirming the Association Between Affective Disturbance and Perceived Cognitive Dysfunction Among Breast Cancer Patients: A Meta-Analysis of Available Literature

Purpose: Breast cancer is the most frequently diagnosed cancer among women worldwide. While undergoing chemotherapy treatment for breast cancer, patients often report experiencing "chemobrain." Previous literature reports correlations between psychological distress and these perceived cognitive problems. The aim of the present study was to examine the strength of the association between affective disturbance and subjective cognitive dysfunction.Methods: This study included a meta-analysis of the literature reporting a correlation between mood and subjective cognitive dysfunction. Eight studies with 1344 breast cancer patients treated with chemotherapy were selected based on stringent study inclusion criteria. Studies reporting a correlation coefficient between mood and subjective cognitive dysfunction were included.Results: In these data, there was no significant correlation between affective disturbance and subjective cognitive dysfunction. A random effects model yielded an overall weighted mean effect size of 0.12.Conclusion: Although this meta-analysis did not confirm the correlation between mood and subjective cognitive dysfunction, there was a clear association between these factors in the original disaggregated analyses, and they are clearly impactful from the time of diagnosis through long-term after care. The clinical implications of the present study and future directions for research are discussed.

Clinical Implications for Working with Gay Men A Self Psychological Treatment Approach.

Specific training for conducting psychotherapy with gay men is limited for psychologists, particularly when using a Self Psychology theoretical orientation (Robertson, 1996). In fact, psychologists often are faced with conflicting and contradictory points of view that mirror society's condemnation of homosexuality (Robertson, 1996). This paper is written from a self-psychological perspective to address the lack of a constructive body of literature that explains the unique treatment needs which impact gay men. Estimates of the prevalence of male homosexuality have generated considerable debate. A common assumption is that there are homosexual and non-homosexual men. However, scientists have long been aware that sexual responsiveness to others of the same sex, like most human traits, is continuously distributed in the population (Michaels, 1996). Still the presumption exists that such traits are stable within each man over time (Michaels, 1996). Conflating same-sex sexual experiences with a categorization of the man as homosexual is problematic, in that defining sexuality solely on the basis of experience excludes people who fantasize about sex with others of the same sex but never have sexual contact. Thus, most modern conceptions of sexual orientation consider personal identification, sexual behavior, and sexual fantasy (McWhirter, Sanders & Reinisch, 1990). Gay men's mental health can only be understood in the context of homosexuality throughout history, since religious and moral objections to sexual attraction between men have existed for centuries. Men who desired other men were regarded as sinful and depraved if not ill or abnormal, and same sex contacts were not distinguished from lewd behaviors (Weeks, 1989). Although most people, regardless of sexual orientation, have experienced some feelings of personal rejection, rarely do heterosexuals become targets for disapproval based on the nature of their attractions and behaviors relative to the same and to the other sex. For lesbians, bisexuals, and gay men, however, homosexuality becomes the focus of aspects of themselves that make them feel hated and hateful (Isay, 1989). While gay men and lesbians are often considered together because of the same-sex nature of their relationships and the similar issues that they may experience in their treatment within society, there are many issues where they might be best studied separately. Issues involving with health, parenthood, sexuality and perceived roles and status in society, for example, are often related more to gender than to any shared concept of a 'gay and lesbian community'. Many issues surrounding lesbians and lesbian culture will have more to do with women's issues, and some issues involving with gay men will have more to do with the gay male subculture and with masculinity. The author of this paper has limited experience in working with lesbian and bisexual individuals, and although it is likely that some of the concepts articulated in this paper could translate to working with lesbian and bisexual individuals, further research is indicated to examine the beneficence of utilizing a Self Psychological orientation in psychotherapy with lesbian women and bisexual individuals. This paper presents an overview of the literature including historical treatments of homosexuality, the history of Self Psychology, key principles in Self Psychology, research on Self Psychology, identity development models for gay men, and Self Psychological perspectives on identity development related to gay men. The literature review is followed by a section on treatment implications for psychologists seeking to treat gay men, including case vignettes based on work from my own practice. I have preserved the anonymity of clients by changing demographics, and rearranging and combining presenting issues and historical backgrounds among the case examples.

The Perceived Effects of Dance for Individuals with Parkinson’s Disease and Healthy Amateurs

The objective of the present study was to compare the effects of dance participation on physical and psychological functioning as perceived by two distinct groups of dancers: dancers with Parkinson's disease (PD) and healthy amateur (HA) dancers. Dancers in the Parkinson's sample group were gathered from participants in the Dance for PD® program, while healthy amateur dancers were recruited from university dance departments and through social media. Both groups were administered measures related to affect, self-efficacy, quality of life, and which aspects of dance classes were most helpful and/or challenging. Several open-ended questions for both groups were included, along with questions specific to each group. Results of the study indicated that there was no difference between the two groups on positive affect experienced while dancing, but that HA dancers experienced higher levels of negative affect than PD dancers. HA dancers exhibited higher levels of self-efficacy, but there was no difference between the groups on perceived quality of life. Additionally, both groups identified the same two components of dance classes as the most helpful: "moving and getting some exercise" and "doing something fun." Thematic analysis of responses to open-ended questions found that, in general, HA and PD dancers identified similar factors which made dance unique from other forms of exercise. The primary differences were that HA dancers more strongly emphasized artistic and spiritual components of dance, whereas PD dancers focused on the importance of the dance instructors and tailoring movements to individuals with PD. More differences were found between the two groups with respect to the negative aspects of dance classes. Notably, PD dancers identified almost no negative aspects, while HA dancers described internal and external pressure, criticism, and competition as problematic. Future research could benefit from ensuring that both groups are administered the same standardized measures to allow for additional comparisons between groups and with normative samples.

Geothermal Electricity Generation in Colorado: Actual and Perceived Obstacles to Greater Implementation

The objective of this paper is to provide an analysis of the potential and obstacles to the development of geothermal energy resources in Colorado. Geothermal energy is the only renewable resource that can provide base-load electricity. While Colorado has significant geothermal energy potential, there are no such power plants. Layers of federal and state laws and regulations represent one barrier to further geothermal development. Transmission constraints represent another major barrier. High exploration and construction costs along with high-risk profiles for geothermal projects form another major barrier. Perceived barriers such as misunderstanding the impacts, risks, and benefits of geothermal energy hinder further development. Recommendations are provided to help overcome these obstacles.