Biomedical subjects

I Caroline Le Poole

Publications and source records attributed to I Caroline Le Poole.

12 recordsLinked to original sources

PubMed2006

Therapeutic implications of autoimmune vitiligo T cells.

Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can re-direct the immune response towards the tumor.

Animals↗

PubMed2005

4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo.

The trigger initiating an autoimmune response against melanocytes in vitiligo remains unclear. Patients frequently experience stress to the skin prior to depigmentation. 4-tertiary butyl phenol (4-TBP) was used as a model compound to study the effects of stress on melanocytes. Heat shock protein (HSP)70 generated and secreted in response to 4-TBP was quantified. The protective potential of stress proteins generated following 4-TBP exposure was examined. It was studied whether HSP70 favors dendritic cell (DC) effector functions as well. Melanocytes were more sensitive to 4-TBP than fibroblasts, and HSP70 generated in response to 4-TBP exposure was partially released into the medium by immortalized vitiligo melanocyte cell line PIG3V. Stress protein HSP70 in turn induced membrane tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and activation of DC effector functions towards stressed melanocytes. Melanocytes exposed to 4-TBP demonstrated elevated TRAIL death receptor expression. DC effector functions were partially inhibited by blocking antibodies to TRAIL. TRAIL expression and infiltration by CD11c+ cells was abundant in perilesional vitiligo skin. Stressed melanocytes may mediate DC activation through release of HSP70, and DC effector functions appear to play a previously unappreciated role in progressive vitiligo.

Adenoviridae↗

PubMed2004

Antitumor efficacy of Venezuelan equine encephalitis virus replicon particles encoding mutated HPV16 E6 and E7 genes.

An effective vaccine for treating human papillomavirus (HPV)-associated malignancies such as cervical cancer should elicit strong T cell-mediated immunity (CMI) against the E6 and/or E7 proteins necessary for the malignant state. We have developed Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) vaccines encoding the HPV16 E6 and E7 genes and tested their immunogenicity and antitumor efficacy. The E6 and E7 genes were fused to create one open reading frame and mutated at four or at five amino acid positions to inactivate their oncogenic potential. VRP encoding mutant or wild type E6 and E7 proteins elicited comparable cytotoxic T lymphocyte (CTL) responses to an immunodominant E7(49-57) epitope and generated comparable antitumor responses in several HPV16 E6(+)E7(+) tumor challenge models: protection from either C3 or TC-1 tumor challenge was observed in 100% of VRP-vaccinated mice. Eradication of C3 tumors was observed in approximately 90% of mice following therapeutic VRP vaccination. Eradication of HLF16 tumors lacking the E7(49-57) epitope was observed in 90% of human leukocyte antigen (HLA)-A(*)0201 transgenic mice following therapeutic VRP vaccination. Finally, the predicted inactivation of E6 and E7 oncogenic potential was confirmed by demonstrating normal levels of both p53 and retinoblastoma proteins in human mammary epithelial cells (MEC) infected with VRP expressing mutant E6 and E7 genes. These promising results support the continued development of mutant E6 and E7 VRP as safe and effective candidates for clinical evaluation against HPV-associated disease.

Animals↗

PubMed2004

Autoimmune aspects of depigmentation in vitiligo.

Autoimmune depigmentation of the skin, vitiligo, afflicts a considerable number of people, yet no effective therapeutic modalities have been developed to treat it. In part, this can be attributed to the obscure etiology of the disease, which has begun to reveal itself only recently. It is known that pigment is lost as a function of reduced melanocyte numbers in the epidermis, and that depigmentation is accompanied by T cell influx to the skin in the vast majority of patients. Characterizing such infiltrating T cells as type 1 proinflammatory cytokine-secreting cells reactive with melanocyte-specific antigen is a major step toward effective therapy. Melanoma research has shown that differentiation antigens, also expressed by normal melanocytes, can be immunogenic when expressed in the melanosomal compartment of the cell. Similar reactivity to melanosomal antigens is apparent for T cells infiltrating vitiligo skin. It may eventually be possible to treat patients with decoy antigens that anergize such Tcells, or to prevent recruitment of the T cells to the skin altogether. In this respect, it is important that T cells are recruited to the skin as a function of dendritic cell activation and that dendritic cells are likely activated at sites of epidermal trauma as a consequence of stress proteins that spill over into the microenvironment. Stress proteins chaperoning antigens representative of the cells from which they were derived are then processed by dendritic cells and contribute to their activation. Activated dendritic cells not only migrate to draining lymph nodes to recruit T cells but may execute cytotoxic effector functions as well. The contribution of the effector functions to actual depigmentation of the skin remains to be investigated.

Autoimmunity↗

PubMed2004

Expression of gp100 and CDK2 in melanoma cells is not co-regulated by a shared promoter region.

Expression of the pigmentation-associated gene PMel17 is regulated by a 1 kB promoter region shared between the PMel17 and CDK2 genes. The encoded melanosomal glycoprotein gp100 and the cell cycle regulatory protein CDK2 are transcribed in opposite directions. Luciferase reporter constructs were generated for subregions of the promoter containing 0, 1, 2 or 3 putative binding sites for transcription factors with basic helix-loop-helix (bHLH) motifs. The potential contribution of bHLH transcription factor microphthalmia transcription factor (MITF) to promoter activity was investigated by re-introducing microphthalmia into melanoma cells lacking expression. A bi-directional reporter construct was generated to investigate potential co-regulation of gp100 and CDK2 transcription. Promoter activity was assessed in presence and absence of phorbol ester tetradecanoyl phorbol 13-acetate (TPA). FACS analysis and immunohistology served to evaluate co-regulation of gp100 and CDK2 expression at the protein level. The full-length promoter, including a consensus binding site for MITF was found to contain sequences that suppressed gp100 expression. Introduction of MITF into non-expressing 1123 melanoma cells did not restore gp100 expression levels. A lack of coregulation for gp100 and CDK2 as suggested by immunostaining was supported by findings of dissimilar expression regulation by TPA for either gene. The current study provides insight into transcriptional regulation of the PMel17 and CDK2 genes, important to identify strategies for modulating expression of gp100 and CDK2 proteins by melanoma cells.

CDC2-CDC28 Kinases↗

PubMed2003

HPV protein/peptide vaccines: from animal models to clinical trials.

Human Papillomaviruses are viruses that infect the epithelial layers of the oral, rectal, vaginal, and cervical mucosa. There is a causal link between the development of cervical cancer and some other cancers and high-risk human papillomavirus infection (1, 2). Currently there is no prophylactic or therapeutic vaccine available against human papillomavirus infection and its associated lesions. In addition, there exists a high degree of species specificity associated with papillomavirus infection precluding human papillomavirus's use in animal models. Therefore, multiple researchers have utilized a variety of homologous animal papillomaviruses and animal model systems for the development of vaccine strategies against papillomaviruses. The goal of their efforts is to identify vaccine strategies that are efficacious in the animal model systems and translate these strategies into human clinical trials against human papillomavirus. The development of such a vaccine would ultimately result in a reduction in the incidence of cervical cancer and some other HPV-linked cancers and may provide therapy for individuals harboring papillomavirus lesions. This review discusses the advances in papillomavirus vaccinology using proteins/peptides, from the work completed in the animal models to the results of the early human clinical trials.

Animals↗

PubMed2003

Cervical cancer vaccines: recent advances in HPV research.

Carcinomas of the anogenital tract, particularly cancer of the cervix, account for almost 12% of all cancers in women, and so represent the second most frequent gynecological malignancy in the world (48). It is well established that chronic infection of cervical epithelium by human papillomaviruses (HPV) is necessary for the development of cervical cancer. In fact, HPV DNA has been demonstrated in more than 99.7% of cervical cancer biopsy specimens, with high-risk HPV16 and HPV18 sequences being most prevalent (45,73). Therefore, an effective vaccine that would mount an immune response against HPV-related proteins might contribute to the prevention or elimination of HPV expressing lesions. This review will concentrate on the most recent advances in vaccine-mediated prevention and immunotherapy of HPV-induced cervical cancer, including presentations from the 20(th) International HPV Conference held in October 2002 in Paris.

Cancer Vaccines↗

PubMed2003

Recent progress in tumour vaccine development.

Immunotherapy offers an exciting opportunity to treat human cancer. Analysis of tumour-associated antigens is progressing. Assisted by animal models, such knowledge can be used to design tumour vaccines. By including adjuvants to increase immunogenicity, several tumours previously thought to be non-immunogenic are now considered targets for tumour vaccines. Newly acquired knowledge regarding dendritic cell physiology is incorporated in newly designed vaccines that are currently in Phase I and II trials. Such assessment provides the overall conclusion that tumour vaccines are safe and deserve a more prominent place in the sequel of treatments for human cancer.

Animals↗

PubMed2003

Advances in prophylactic cancer vaccine research.

Prophylactic vaccination against human cancer provides a unique opportunity to prevent human suffering for individuals at risk for tumor development. Appropriate vaccines may pose slightly different requirements than vaccines intended for therapeutic use. Prophylactic vaccines will need to prevent tumors far into the future, emphasizing the need to establish solid tumor-specific immunologic memory. Another important issue associated with prophylactic cancer vaccines is the identification of appropriate populations for vaccination. Individuals at risk may include those exposed to oncogenic viruses, those with occupational exposure to tumor promoting agents, and individuals with a family history of cancer. This paper addresses the specific challenges posed to the exciting field of prophylactic cancer vaccine research.

Animals↗

PubMed2002

Interferon-gamma reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells.

In malignant melanoma, tumor-infiltrating lymphocytes are frequently reactive with melanosomal antigens. Achieving complete remissions by peptide therapy is frequently hampered by metastases evading immune recognition. The tumor microenvironment seems to favor reduced expression of target antigens by melanoma cells. Among candidate factors, interferon-gamma (IFN-gamma) (10(2) to 10(3) U/ml) suppressed expression of antigens MART-1, TRP-1, and gp100 by M14 melanoma cells as shown by immunohistology and fluorescence-activated cell sorting analysis, reducing MART-1 expression by >65%. Northern blot analysis revealed that reduced expression was regulated at the transcriptional level, demonstrating a 79% reduction in MART-1 transcript abundance after 32 hours of IFN-gamma treatment. To evaluate consequences of IFN-gamma exposure for immune recognition, MART-1-responsive T cells were reacted with pretreated HLA-matched melanoma cells. Cytotoxicity was reduced up to 78% by IFN-gamma pretreatment, and was restored by addition of MART-1 peptide AAGIGILTV for 2 hours. Examination of melanoma lesions by quantitative reverse transcriptase-polymerase chain reaction revealed up to 188-fold more abundant IFN-gamma transcripts when compared to control skin. Laser capture microdissection and immunohistology localized most IFN-gamma-producing T cells to the tumor stroma. Reduced MART-1 expression was frequently observed in adjacent tumor cells. Consequently, IFN-gamma may enhance inflammatory responses yet hamper effective recognition of melanoma cells.

Antigens, Neoplasm↗

PubMed2002

Emerging strategies in tumor vaccines.

Reports of novel developments in tumor vaccines that have appeared in the year ending May 1, 2002 are reviewed here. Antigenic moieties were revealed for tumors previously considered nonimmunogenic. The use of peptides spanning mutations detected exclusively in tumor tissue avoids the common concern for autoimmune responses. Carbohydrate biology is revealing novel antigenic moieties. The search for helper epitopes from tumor antigens has come into full swing. Humoral immunity is regaining terrain, particularly through the development of antiidiotypic antibodies. Major steps forward have been made in optimizing modes and routes of antigen delivery and in the use of immune adjuvants. In the clinic, phase I/II trials support the notion that tumor vaccines are safe. Because these trials are conducted in patients in whom tumor remission is not a realistic endpoint, patient responses were established by immune monitoring strategies to detect subtle changes in antitumor reactivity. Both clinical and laboratory data stress the vast potential of tumor vaccines for the treatment of cancer.

Adjuvants, Immunologic↗

PubMedDate not supplied

T-cell avidity and tuning: the flexible connection between tolerance and autoimmunity.

Thymic T-cell selection mechanisms generate a cross-reactive, self-MHC restricted peripheral T-cell pool. Affinity and avidity are of profound influence on this selection and the generation of immunity. Autoreactive T cells can escape thymic deletion by lowering their avidity and retain this "tuned" state in the periphery. Upon activation, tuned T cells can cause autoimmunity, while immunotherapeutic strategies may be hampered by existing T-cell tolerance. The regulation of T-cell avidity and tuning therefore determines the balance between tolerance and autoimmunity and should be taken into account in the design of therapeutic strategies aimed at T-cell reactivity.

Animals↗