CD4+ T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4+ T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, κ) against CD4, was studied in a human psoriasis xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4+, but not CD8+ CD3+ T cells. The capacity of Zanolimumab to deplete the CD4+ T cells in the skin may be of importance in diseases where CD4+ T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody is currently in a phase III clinical trial for CTCL, a disease for which there is no safe and effective treatment available today.

APMISVolume 115, Issue 5 p. 604-606 Heterotransplantation Of A Human Malignant Tumour To "Nude" Mice First published: 11 May 2007 https://doi.org/10.1111/j.1600-0463.2007.apm_689a.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume115, Issue5May 2007Pages 604-606 RelatedInformation

Most nude mice do not allow the formation of metastases after heterotransplantation of human malignant tumours. Here we describe a substrain of BALB/c nude mice (BALB/c/AnNCr) that reproducibly allows some human cancers to metastasize. By Mendelian analysis of hybrids between this substrain and C57BL/6J +/+ mice we found that the ability to allow a human tumour (MDA‐MB‐435 BAG) to express its metastatic phenotype is determined by a recessively inheritable trait in the mouse host. We are presently working to identify the genetics responsible for development of metastases. The study also includes immunohistochemical and electron microscopic analysis of the test tumour, originally assumed to be a human mammary carcinoma, but shown to possess characteristics of a malignant melanoma (1). The ultimate aim of our ongoing study is to establish a substrain of nude mice that will allow metastasis in all recipients.

Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had approximately 1.2 days doubling time with loss of contact inhibition. All retained 1,25-(OH)(2) vitamin D(3)-induced expression of osteoblastic markers: collagen type I, alkaline phosphatase, and osteocalcin. All shared INK4a/ARF gene locus deletion and epigenetic silencing of the DBCCR1 tumor suppressor gene. Despite in vitro commonality, only four of six clones shared the growth kinetics and 100% tumorigenicity of the parental population. In contrast, one clone consistently formed latent tumors and the other established tumors with only 30% penetrance. Changing the in vitro microenvironment to mimic in vivo growth aspects revealed concordant clonal heterogeneity. Latent tumor growth correlated with extracellular matrix entrapment of multicellular spheroids and high procollagen type III expression. Poor tumorigenicity correlated with in vitro serum dependence and high p27(Kip1) expression. Aggressive tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer.

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-gamma, TNF-alpha, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb's using human immunoglobulin-transgenic mice. One of the IL-15-specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor alpha, beta, gamma complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF-alpha release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15-specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.

Background Apoptosis has been proposed to act as an important mechanism for eliminating keratinocytes that have been irreversibly damaged by ultraviolet (UV) irradiation. One way to induce apoptosis in keratinocytes is through activation of the cell surface receptor Fas (CD95), either with the ligand (FasL) or directly with UV radiation.Objectives To investigate the regulation of Fas and FasL expression in human skin and the formation of apoptotic cells after in vivo exposure to UVB or long-wave UVA radiation.Methods Volunteers were irradiated with either 3 minimal erythema doses (MED) of UVB (n = 6) or 3 MED of long-wave UVA (n = 6) on buttock skin 12, 24 and 72 h before skin punch biopsies were taken. Expression of Fas and FasL was demonstrated by immunohistochemistry on cryostat sections. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated fluorescein-deoxyuridine triphosphate nick-end labelling reaction.Results In five of six subjects, exposure to UVB radiation resulted in increased homogeneous expression of Fas on epidermal cells, with greatest expression at 24 and 72 h after irradiation. In all subjects, exposure to long-wave UVA resulted in increased homogeneous expression of Fas on epidermal cells, with greatest expression at 12 h after irradiation. In five of six subjects, exposure to UVB radiation resulted in temporarily decreased expression of FasL, but after 72 h the expression of FasL had returned to the preirradiation level. The expression of Fast, on epidermal cells after exposure to long-wave UVA showed considerable variation. UVB irradiation was a stronger inducer of epidermal apoptosis than was UVA irradiation. The number of apoptotic epidermal cells did not correlate with expression of Fas or FasL.Conclusions In human skin the expression of Fas on epidermal cells increases after in vivo exposure to UVB or long-wave UVA. Exposure to UVB causes a temporary decrease in the expression of FasL on epidermal cells.

The benefits of moisture-retaining dressings on wound healing are well documented in experimental animal models but not in humans. To examine the effect of occlusion, the effects of three brands of synthetic occlusive dressings (Comfeel Plus, DuoDerm CGF, OpSite) were compared with air exposure in epithelial resurfacing and proliferation in acute, full-thickness skin wounds in humans. In 10 healthy males, four 4 mm standardised wounds were made with a sterile punch biopsy on each lower extremity. Epithelialisation of the wounds was assessed histologically and blindly postwounding on days 7 and 14. Wound margin epidermal proliferation was evaluated immunohistochemically with Ki67. Epithelial percentage coverage increased significantly (p = 0.007) with the occlusive dressings (62 +/- 6%, mean +/- SEM), compared with air exposure, (39 +/- 7%) on day 7 but not on day 14 (p = 0.500). Epidermal cell proliferation showed no significant intergroup difference on either day. Treatment with occlusive dressings increased early epithelial migration of acute full-thickness biopsy wounds compared with air exposure in healthy men.

The cystic variant of vestibular schwannoma (VS) presents a therapeutic dilemma. Several studies have previously demonstrated that the surgical outcome in this tumour entity is less favourable than that of solid tumours of comparable size. The "wait and scan" policy has not been recommended for these tumours, as the cystic elements expand, causing displacement of the brainstem and compression of the 4th ventricle, resulting in hydrocephalus. The large tumour size at diagnosis and the cystic contents do not support the role of radiosurgery as a therapeutic option. We have previously published the surgical outcome of 23 cystic VS. The present study includes 44 patients (44 cystic tumours) in a series of 773 tumours (5.7%) who underwent surgery in the period 1976 to 1996. This paper presents the neuroradiological and histological features of the tumours, as well as the results of tumour specimen implantation and surgery in athymic nude mice. Therapeutic options are also discussed.

APMISVolume 107, Issue 1-6 p. 1-1 APMIS 1924–1999 Seventy five years in the service of science Jørgen Rygaard, Jørgen Rygaard Editor-in-chiefSearch for more papers by this author Jørgen Rygaard, Jørgen Rygaard Editor-in-chiefSearch for more papers by this author First published: 15 August 2009 https://doi.org/10.1111/j.1699-0463.1999.tb01519.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume107, Issue1-6March 1999Pages 1-1 RelatedInformation

Mucin-type O-glycosylation is initiated by a large family of UDP-GalNAc: polypeptide N -acetyl-galactosaminyltransferases (GalNAc-transferases). Individual GalNAc-transferases appear to have different functions and Northern analysis indicates that they are differently expressed in different organs. This suggests that O-glycosylation may vary with the repertoire of GalNAc-transferases expressed in a given cell. In order to study the repertoire of GalNAc-transferases in situ in tissues and changes in tumors, we have generated a panel of monoclonal antibodies (MAbs) with well defined specificity for human GalNAc-T1, -T2, and -T3. Application of this panel of novel antibodies revealed that GalNAc- transferases are differentially expressed in different cell lines, in spermatozoa, and in oral mucosa and carcinomas. For example, GalNAc-T1 and -T2 but not -T3 were highly expressed in WI38 cells, and GalNAc-T3 but not GalNAc-T1 or -T2 was expressed in spermatozoa. The expression patterns in normal oral mucosa were found to vary with cell differentiation, and for GalNAc-T2 and -T3 this was reflected in oral squamous cell carcinomas. The expression pattern of GalNAc-T1 was on the other hand changed in tumors to either total loss or expression in cytological poorly differentiated tumor cells, where the normal undifferentiated cells lacked expression. These results demonstrate that the repertoire of GalNAc-transferases is different in different cell types and vary with cellular differentiation, and malignant transformation. The implication of this is not yet fully understood, but it suggests that specific changes in sites of O-glycosylation of proteins may occur as a result of changes in the repertoire of GalNAc-transferases.

Using confocal laser scanning microscopy we studied sections of the T24B, a human bladder carcinoma, grown in C.B.-17 scid/scid or NMRI nu/nu mice in order to examine the relationship between tumor tissue and tumor vessles. Tumor cells were labelled with FITC-anti-cytokeratin and blood vessel endothelia with Cy3-labelled BS-I lectin. In constrast to our expectation, no major leaks in the endothelial lining of blood vessels were observed. We are looking for a suitable marker for mouse lymphatics in order to investigate their possible role.

The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non‐lethal dose of S. typhimurium. Four weeks after the infection, spleen non‐adherent mononuclear cells were isolated. The cells were separated according to their expression of CD4 and the OX40 antigen by FACS. OX40+ and OX40− CD4+ T‐cell subpopulations were together with unsorted CD4+ T cells transferred to untreated rats 24 h prior to infection with S. typhimurium. Transfer of either unsorted CD4+ T cells or CD4+ T cells sorted into OX40− or OX40− subpopulations significantly increased animal survival compared to controls. Animals receiving OX40+CD4+ T cells did not differ significantly in survival probability from those receiving unsorted CD4+ T cells. However, animals receiving OX40−CD4+ T cells had a significantly better survival compared to animals given unsorted CD4+ T cells. It is concluded that OX40−CD4+ T cells can induce significant protection against S. typhimurium infections in rats. This is most likely due to the fact that the OX40−CD4+ T‐cell population contains a significant number of antigen‐specific memory T cells that have returned to a resting state.

With the aim of studying possible T‐cell mediated selection of the cells in growing tumours, 108 mice of the C.B‐17 strain, either immunocompetent C.B‐17 mice or histocompatible immunodeficient C.B‐17 severe combined immune deficiency (scid) were treated with 3‐methylcholanthrene (MCA) in two different dosages. A total of 51 tumours were obtained, 44 of which were established as uncloned tumour cell lines, and used for further study. Tumour incidence correlated with carcinogen‐dosage in that more tumours developed in groups treated with a high MCA dose than in groups treated with a low MCA dose, but not with immune status of the tumour host. No significant difference in the level of MHC class I molecule expression was found between the two groups of tumours. The rate of rejection after transplantation to syngeneic immunocompetent hosts was significantly higher for the scid tumours than for the non‐scid tumours. The authors suggest that this reflects an immunoselection performed by T cells in the immunocompetent host in which the tumour originated, which has eliminated highly immunogenic tumour cells, leaving non‐immunogenic tumour cells to grow.

The cytotoxicity of NK cells and lymphocytes derived from nonadherent splenocytes (SPL) and regional lymph node cells (LNC) from complete Freund's adjuvant (CFA)‐treated athymic nude young (4–6 weeks) and aged (over 1 year) BALB/c nu/nu mice in vitro activated with rIL‐2, anti‐CD3 mAb or PPD was analyzed and compared to SPL and LNC from age‐matched euthymic BALB/c mice. The high natural cytotoxicity to YAC‐1 target cells of SPL or LNC could be augmented by 48 h stimulation in vitro with rIL‐2, especially when derived from young nude BALB/c mice. The increase in cytotoxic activity was accompanied by increased proliferative activity of both SPL and LNC, which showed statistically significant differences between the rates of stimulation of cells from the young and aged groups. Anti‐CD3 mAb strongly activated the cytotoxicity of BALB/c euthymic donor effector cells against P‐815 target cells, corresponding to a very high proliferative activity of these cells, but anti‐CD3 mAb did not lead to activation of effector cells from nude donors. FACS analyses of antigenic markers similarly showed an increased number of T cells in LNC from aged BALB/c nude donors, which, however, never reached the levels of those of euthymic animals.

Nerve growth factor (NGF) has the potential to induce cellular differentiation in various neoplastic and non-neoplastic cell lines. The purpose of the present study was to determine by immunohistochemistry: the presence/distribution of nerve growth factor receptor (NGFr), cellular proliferation expressed by Ki-67, and intratumoral vascularization visualized by the endothelial marker CD 31, in a series of 61 human vestibular schwannoma heterotransplants in athymic nude mice. The immunohistochemical results were correlated to the observed macroscopic growth in 22 heterotransplants (36%) with obvious macroscopic growth, versus 39 heterotransplants (64%), that were stationary or regressed. The positive immunoreactivity to NGFr, number of Ki-67 positive nuclei and number of intratumoral vessels were significantly higher in the 22 (36%) growing heterotransplants than in the 39 heterotransplants (64%), which were stationary or regressed (p < 0.00005, p = 0.046, p < 0.00001). NGFr was statistically related to the vascularity of the heterotransplants expressed by CD 31 (p<0.00001). No significant relation was observed between NGFr and the proliferation, as estimated by Ki-67. The results revealed that the macroscopic growth of VS in athymic nude mice was associated with strong positive expression of NGFr, high cellular proliferation expressed by Ki-67 and vivid neovascularization expressed by CD 31. The possible clinical applicability of the achieved results is discussed.