bluuebunny/crossref_metadata_2025 huggingface dataset:
Confocal laser scanning microscopy: a new optical microscopic technique for applications in pathology and dermatology
Authors: Fink‐Puches R. , Hofmann‐Wellenhof R. , Smolle J. , Kerl H.
Published: April 2006

Confocal laser scanning microscopy (CLSM) is a new optical microscopic technique, which offers significant advantages over conventional microscopy. CLSM is microscopy of optical sections. Light, which is emitted from regions other than the focal plane, is cut off by introducing a diaphragm in the beam path. The result is an optical “slice”, which shows more details because the blurring from out of focus haze disappears. It has been repeatedly used in experimental, but also in diagnostic dermatopathology. The “in vivo” confocal microscopy, applied directly to the intact skin provides details of living cells in the superficial layers comparable to that of fixed and stained tissue. While the extent of its future applications is hard to predict, its potential for applications in dermatology appears enormous, particularly for studies of fixed or living tissues, where it is desirable to obtain clear images many micrometers below the surface of the tissue under examination.
Histopathologic features seen in sulfur mustard induced cutaneous lesions in hairless guinea pigs
Authors: Smith K.J. , Graham J.S. , Moeller R.B. , Okerberg C.V. , Skelton H. , Hurst C.G.
Published: April 2006

Sulfur mustard (SM), a chemical warfare agent first used early in the 20th century, has re‐emerged in the past decade as a major threat around the world. At present, there are no effective therapeutic measures for SM exposure. Because the skin as well as other interface epithelial surfaces are the first tissues effected as this agent is absorbed, reactions within the skin are an area of active research into the mechanism of action of this alkylating agent. The euthymic hairless guinea pig has been used as the animal model for the study of SM induced injuries because of morphologic similarity of its skin to human skin, with a multiple layer epidermis, and because this animal has a normal immune system. We reviewed 102 biopsy specimens from 51 animals exposed to three different dose times of saturated SM vapor. Histopathologic evidence exists for increased programmed cell death as well as cellular necrosis, subepidermal blister formation, and delayed re‐epithelialization secondary to problems with adhesion. Information obtained from this study adds to the body of information important in the investigation of the mechanisms of action of SM.
Pigmented epidermotropic ductal carcinoma of the breast in a male
Authors: Fernández‐Figueras M. T. , Puig L. , Casanova J. M. , Musulén E. , Matías‐Guiu X. , Navas‐Palacios J. J.
Published: April 2006

The first case of pigmented epidermotropic breast carcinoma in a male, presenting as a pigmented lesion of the areola and nipple, is described. Immunohistochemical and ultrastructural studies demonstrated that the pigmentation was found to be primarily due to colonization of tumor nests by melanocytes, with numerous melanophages interspersed in the desmoplastic stroma and only occasional compound melanosomes within the epithelial tumor cells.
Multiple tumors of follicular infundibulum with sweat duct differentiation
Authors: Horn Thomas D. , Vennos Elizabeth M. , Bernstein Benjamin D. , Cooper Philip H.
Published: April 2006

A 67‐year‐old man is reported with multiple tumors of follicular infundibulum containing ducts. Approximately 30 hypopigmented, scaling macules and minimally elevated papules were present on the face. Skin biopsy specimens from 5 representative lesions revealed similar findings. There was a proliferation of ramifying strands of pale‐staining keratinocytes in the upper dermis showing connections with follicular infundibula of vellus follicles and epidermis. There was evidence of hair follicle differentiation with small follicular bulbs, papillary mesenchymal bodies, keratocysts, and occasional hair shafts in the tumor. These findings are characteristic of prior reports of TFI. Ducts were also present within the epithelial cords. Carcinoembryonic antigen, gross cystic disease fluid protein‐15, epithelial membrane antigen, and S‐100 protein were identified within the tumor. We theorize that the ductal elements within these TFI reflect the multipotential differentiating capacity of portions of infundibular epithelium.

Horn TD, Vennos EM, Bernstein BD, Cooper PH. Multiple tumors of follicular infundibulum with sweat duct differentiation.
Immunohistochemical assessment of tumor vascularity in recurrent Clark II melanomas using antibody to type IV collagen
Authors: Guffey J.M. , Chaney J.V. , Stevens G.L , Schroer K.R. , Fenske N.A. , Reintgen D. , Glass L.F.
Published: April 2006

Thin melanomas, measuring 0.76 mm or less, are generally associated with an excellent prognosis. However, a certain subset, of these seemingly innocuous lesions have been reported to develop recurrences. Therefore, the predictive values of currently accepted prognostic indicators have been questioned in thin melanomas. Several studies concerning tumor vascularity in melanoma and certain non‐melanocytic malignancies suggest that the degree of vascularization correlates with growth rate and biologic aggressiveness. In the present study, we determined the vascularity of a small group of Clark level II melanomas that resulted in recurrence, and compared these results to au equal number of nonrecurrent lesions with similar prognostic indicators. Blood vessels were labeled by immunoperoxidase staining techniques for Type IV collagen, and quantified by image analysis. No statistical difference was found between the two groups when mean blood vessel counts and percent vascular area were measured. The recurrent tumors had a mean PVA of 4.68 compared to 4.34 for the nonrecurrent group (p = 0.677). The mean blood vessel count beneath the recurrent group was 29.6 per 400 × field, and the corresponding value for the nonrecurrent group was 31.8 (p = 0.681). Our data is preliminary within this limited group of tumors, yet it suggests that tumor vascularity is not a distinctive prognostic indicator by which eventual outcome can be predicted in thin Clark level II malignant melanomas.
Ultrastructural spectrum of cutaneous nerve sheath myxoma/cellular neurothekeoma
Authors: Argenyi Z.B. , Kutzner H. , Seaba M.M.
Published: April 2006

The histogenesis of cutaneous nerve sheath myxoma (NSM)/ cellular neurothekeoma (CNT) is still controversial. In this study, we examined the ultrastructural features of 16 NSM (3 classical, 11 CNT, and 2 mixed NSM/CNT). We classified the cells into 4 groups ultrastructurally. Type 1 cells were un‐differentiated polygonal cells with ovoid nuclei, cytoplasmic microfilaments, and occasionally with microfilament‐associated dense bodies. In most cells, the cytoplasmic membrane showed focal membranous densities and occasional basal‐lamina‐like material. This cell type comprised approximately 90% of CNT. Type II cells were more differentiated, had ovoid or spindled shapes, were rich in intracytoplasmic filaments, and were surrounded by continous basal lamina. These cells were consistent with Schwann cells and were present in the classical and mixed forms of NSM, and in a single case of CNT. Type III cells had features of perineurial cells and were relatively rare in classical NSM. Type IV cells resembled fibroblasts and were encountered in all variants of NSM. These results support the‐view that 1) the classical NSM has neural (mainly Schwann cell) differentiation, 2) CNT is predominantly composed of undifferentiated cells with partial features of Schwann cells, smooth muscle cells, myofibroblasts and fibroblasts, suggesting a divergent differentiation, and 3) CNT and NSM represent a histologic spectrum, but in CNT, the neural features are not fully expressed.
Expression of androgen receptors in skin appendage tumors: An immunohistochemical study
Authors: Shikata Nobuaki , Kurokawa Ichiro , Andachi Hiromu , Tsubura Airo
Published: April 2006

Androgen receptor (AR) expression was examined in normal skin and in 52 cases of various skin appendage tumors using a monoclonal antibody (F39.4.1) raised against the N‐terminal domain of human AR. Microwave oven heating in citrate buffer solution followed by immunostaining with the labeled streptavidin biotin (LSAB) method was applied to formalin‐fixed paraffin‐embedded sections. Immunoreactive AR was restricted to the nuclei. In normal skin, AR was consistently localized in seboblasts and in some differentiated sebocytes, and variable expression was seen in luminal epithelial cells of eccrine and apocrine glands in the secretory portion. Hair follicles and epidermis showed no reactivity. In sweat gland tumors, AR was identified locally in inner layer cells of the tubuloglandular component of ten of thirteen chondroid syringomas but the remaining tumors were nonreactive. In sebaceous gland tumors, benign tumors with mature sebaceous elements (sebaceous nevi and sebaceous adenomas) showed AR expression, but the sebaceous epitheliomas and sebaceous carcinomas lost their expression. No AR expression was observed in hair follicle tumors, except in AR‐positive mature sebaceous glands incorporated into the cyst wall of steatocystomas.
Outcome of facial rashes with non‐specific histological features: a long‐term follow‐up of 64 cases
Authors: Rhodes Lesley E. , Parslew Richard A. G. , Ashworth John
Published: April 2006

Facial inflammatory dermatoses can be difficult to diagnose in their early stages; skin biopsy may help but often shows indeterminate features. The aims of our study were to identify patients presenting with a facial dermatosis requiring skin biopsy, in whom the initial histological features were classified as “non‐specific”, to determine the eventual diagnostic outcome, and to attempt to identify subtle early histological features. We located 79 such cases with indeterminate histology from 45,000 dermatopathology reports 1972‐1987. The original biopsies were assessed and scored using a check‐list of 20 features and the patients' case‐records up to 1992 were examined. Follow‐up information was available in 64 cases and an eventual clinical diagnosis was made in 54 (84%) of these; the commonest diagnoses were rosacea (26%), chronic discoid lupus erythematosus (24%) and seborrheic or unclassified dermatitis (17%). Histological differences were seen in the original biopsies of these three diagnostic categories, although none was predictive. We conclude that clinical follow‐up leads to the diagnosis of most facial rashes initially showing “nonspecific” histology.
Human parvovirus B19 infection: Immunohistochemical and electron microscopic studies of skin lesions
Authors: Takahashi M. , Ito M. , Sakamoto F. , Shimizu N. , Furukawa T. , Takahashi M. , Matsunaga Y.
Published: April 2006

Erythema infectiosum is known to be caused by human parvovirus B19 and shows characteristic clinical skin manifestations in children, although adult cases of human parvovirus B19 infection do not always show such characteristic features. Recently, we experienced an epidemic adult cases of human parvovirus B19 infection and examined the erythematous skin lesion by immunohistochemistry and electron microscopy to clarify the pathogenesis of the skin manifestations. Light microscopic examination showed slightly irregular‐shaped vessels in the dermis. By immunohistochemistry, using anti‐human parvovirus B19 monoclonal antibody, positive reactions were found in endothelial cells. No immunoglobulins were found, but C3 deposits were present in the perivascular areas. By electron microscopy, virus particles were found in the cytoplasm of endothelial cells. An inflammatory reaction due to the direct human parvovirus B19 infection in dermal vessels seems to be an important factor in the pathogenesis of the skin manifestations.
Solitary reticulohistiocytoma in pregnancy: Immunohistochemical and ultrastructural study of a case with unusual immunophenotype
Authors: Hunt Steven J. , Shin Sung S.
Published: April 2006

A case of a solitary reticulohistiocytoma during pregnancy is reported. The tumor arose on the right thigh of a 31‐year‐old woman during the 2nd month of gestation. Physical examination 6 months later revealed a 9 × 6 mm yellowish white papule. A biopsy showed a dermal proliferation of spindle to polygonal cells embedded in fibrous tissue with admixed neutrophils, eosinophils, and lymphocytes. Immunohistochemistry was positive for S‐100, factor XIIIa, HLA‐DR, KP‐1, vimentin, and neuron‐specific enolase. Ultrastructurally, the cells showed abundant lipid, lysozomes, and endoplasmic reticulum. No Birbeck granules could be identified. The results suggest an aberrant immunophenotype intermediate between indeterminate cells and dermal dendritic cells. The relationship of these lineages to reticulohistiocytoma and other dermal proliferative disorders is reviewed.
Massive papillary dermal fatty infiltration in a patient with psoriasis
Authors: Lee J. , Bhawan J. , Rothman K.
Published: April 2006

A 36‐year‐old Caucasian man presented with chronic, slightly erythematous, scaly plaques of 6 years duration. Some improvement was noticed alter treatment with topical steroids. Differential clinical diagnoses included psoriasis and eczema. A biopsy revealed psoriasiform changes with “fatty vacuoles” replacing the papillary dermis. The histogenesis of these findings is unknown. Even though small foci of fatty vacuolization have been observed in association with heavy inflammatory infiltrates in skin, this is the first reported case of massive fatty infiltrates in a non‐neoplastic disorder of the skin associated with only sparse inflammatory infiltrate.
Expression of the mast cell growth factor interleukin‐3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression
Authors: Reed Jon A. , McNutt N. Scott , Bogdany Jennifer K. , Albino Anthony P.
Published: April 2006

The molecular events responsible for tumor progression in human cutaneous malignant melanoma remain unclear; however, critical to the process is the dysregulated proliferation of tumor cells and the development of new vascular channels which allow further growth and dissemination. Connective tissue mast cells (MC) have been implicated in tumor progression because they concentrate around tumors (including melanomas) prior to the formation of new blood vessels, and because they contain many chemical mediators, including basic fibroblast growth factor (bFGF), known to have mitogenic and angiogenic effects. Several MC chemotactic and mitogenic factors have been described including interleukin‐3 (IL‐3). In order to determine whether there is a differential expression of this MC chemotactic/mitogenic factor with tumor progression in vivo, we evaluated by immunohistochemistry 85 melanocytic lesions including primary invasive malignant melanoma (PIMM), melanoma in situ (MMIS), and ordinary intradermal benign melanocytic nevi (BMN) for expression of IL‐3. Nucleic acid in situ hybridization also was used to evaluate the melanocytic lesions for IL‐3‐specific mRNA transcripts. Intracellular IL‐3 protein was detected in 29/33 (88%) PIMM and 15/25 (60%) MMIS, but was not detected in any (0/27; 0%) BMN (p<0.0001). IL‐3‐specific mRNA transcripts were present in 3/4 PIMM and 2/10 MMIS in which IL‐3 protein was not identified, but were not detected in any BMN. IL‐3 mRNA or protein was not detected in normal melanocytes present in the perilesional epidermis of any of the specimens studied. Immunohistochemistry also was used to confirm the presence of IL‐3α‐specific receptors on human cutaneous MC. As demonstrated by others, a significantly increased number of MC was present in the perilesional stroma of PIMM and MMIS vis à vis BMN (p<0.0001). The results suggest that melanoma cells may attract MC in vivo by producing MC chemotactic/mitogenic factors such as IL‐3. The recruitment of MC and the subsequent release of their potent mitogenic and angiogenic factors such as bFGF may thus represent a tumor–host interaction which favors tumor progression.
Ultrastructural localization of carcinoembryonic antigen (CEA) glycoproteins and epithelial membrane antigen (EMA) in normal and neoplastic sweat glands
Authors: Metze D. , Luger T. A.
Published: April 2006

Glycoproteins of the carcinoembryonic antigen family (CEA) and epithelial membrane antigen (EMA) are established markers for glandular and mucosal tissues. However, their precise ultrastructural distribution in sweat glands has not been determined as yet. Therefore, normal human skin, 19 cases of various sweat gland neoplasms, Paget's disease, and cutaneous metastases of visceral carcinomas were stained with well‐defined antibodies using a postembedding immunogold technique. In some cases, a new method of re‐embedding paraffin material for immunoelectron microscopy was applied. In normal sweat glands, immunoreactivity of the endoplasmic reticulum and vesicles indicated biosynthesis and processing of CEA and EMA. Along the luminal surfaces both CEA and EMA represented an integral part of microvilli. However, a differential expression of CEA and EMA was demonstrated in apocrine epithelia, mucous cells of eccrine glands, and sweat ducts. In fetal glands, CEA was associated with formation of secretory and ductal lumina. The overall cellular distribution of CEA and EMA was highly preserved in benign sweat gland neoplasms whereas malignant neoplasms were characterized by loss of protein targeting and cellular polarity. In conclusion, these immunoelectron microscopical findings suggest a role of CEA and EMA for cell differentiation and secretory mechanisms of sweat gland epithelia.
Mitotic granuloma annulare: a clinicopathologic study of 20 cases
Authors: Trotter Martin J. , Crawford Richard I. , O'Connell John X. , Tron Victor A.
Published: April 2006

The finding of mitotic figures in granuloma annulare (GA) has not been emphasized in the literature. We describe 20 cases of a cellular, mitotically active variant of GA; we defined this group as cases having ≥ 1 mitosis per 10 hpf. Clinically, the lesions could not be distinguished from typical, localized GA: there were 9 males and 11 females with a mean patient age of 49±15 years (mean±SD), compared to 45±20 years in a randomly selected control group of 60 patients with GA, and no unusual sites of predilection were noted. Histologically, a classic, palisading granuloma pattern predominated (18/20 cases). Lesions were located in the mid‐dermis and tended to be more cellular than typical GA. The histiocytes comprising the lesion often had enlarged nuclei and prominent nucleoli. The number of mitoses per 10 hpf was 3.0±1.5 (range 1.0–7.2), control group 0.3±0.5; occasional atypical mitotic figures were observed. The proliferative nature of these lesions was confirmed using MIB‐1 staining; the percentage of MIB‐1 positive cells ranged from 5%–29% (mean 15±6%). Mitotic GA must be distinguished histologically from neoplastic processes, in particular epithelioid sarcoma. We conclude that histiocytes in clinically typical GA can exhibit an increased mitotic rate. Recognition of this variant is important in order to avoid overdiagnosis of a malignant condition.
Dermatofibroma with granular cells
Authors: Val‐Bernal J. Fernando , Mira Concepción
Published: April 2006

A new histologic variant of dermatofibroma, only briefly alluded to in dermatological literature is reported. This tumor was located in the back of a 24‐year‐old man. It was present for about 2 years and had a history of trauma 2 months before excision. The lesion showed similar characteristics to those of conventional dermatofibroma as well as the presence of groups of granular cells identical to those seen in granular cell tumors. It is important to recognize dermatofibroma with granular cells because it may be confused with a variety of benign or malignant soft tissue tumors containing similar granular cells that entail different significance or prognosis. The immunohistochemical study supports a granular cell change in a dermatofibroma instead of a granular cell tumor that has been traumatized, with secondary formation of a dermatofibroma reaction.
Dermatomal lichenoid chronic graft‐vs‐host disease following varicella‐zoster infection despite absence of viral genome
Authors: Baselga Eulalia , Drolet Beth A. , Segura Annette D. , Leonardi Craig L , Esterly Nancy B.
Published: April 2006

Localized cutaneous graft‐versus‐host disease (GVHD) following a dermatomal distribution or in a pattern of Blaschko's lines. Some authors have postulated that dermatomal GVHD is triggered by a varicella‐zoster virus infection, although in reported cases, there was no history of a preceding herpes zoster. We describe a case of GVHD localized to the exact dermatome of a culture‐proven varicella‐zoster virus infection. PCR analysis failed to detect persistence of viral genome in the affected skin.
From stem cells to lymphocytes; biology and transplantation
Authors: Aguila Hector L. , Akashi Koichr , Domen Jos , Gondy Kimberly L. , Lagasse Eric , Wright Douglas E. , Wassman Irving L. , Morrison Scan J. , Mebius Reina E. , Shizuu Judy , Strober Samuel , Uchida Nohuko
Published: April 2006

Summary: We review the development of the hematopoietic system, focusing on the transition from hematopoietic stem cells (HSCs) to T cell This includes the isolation of HSCs, and recent progress in understanding their ontogeny, homing properties, and differentiation. HSC transplantation is reviewed, including the kinetics of reconstitution, engraftment across histocompatibility barriers, the facilitation of allogeneic engraftment, and the mechanisms of graft rejection. We describe progress in understanding T‐cell development in the bone marrow and thymus as well as the establishment of lymph nodes. Finally, the role of bcl‐2 in regulating homeostasis in the hematopoietic system is discussed.
Delineation of the human hematolymphoid system: potential applications of defined cell populations in cellular therapy
Authors: Chen Benjamin P. , Galy Anne M. , Fraser Christopher , Hill Beth
Published: April 2006

Summary: Hematopoietic stem cells (HSC) have the capacity to reconstitute ail the blood cells in the body HSC are rare, representing on average 0.0 5% of the mononuclear cells present in healthy human bone marrow. Due to their capacity for self–renewal and their pluripotent, long–term reconstituting potential. HSC are considered ideal for transplantation to reconstitute the hematopoietic system after treatment for various hematologic disorders or as a target for the delivery of therapeutic genes. Human HSC also have potential applications in restoring the immune system in autoimmune diseases and in the induction of tolerance for allogeneic solid organ transplantation. With the increased interest in human HSC for clinical applications, technology for the isolation of candidate HSC and knowledge of human hematopoiesis have been growing rapidly. In this article, we discuss the functional characterization of a human CD34+ Thy‐1+ HSC population which is essentially free of residual disease, our efforts to generate alternate monoclonal antibodies for the isolation of clinically useful stem or progenitor cell populations, and the identification of a novel lymphoid progenitor as part of an exploration towards defining progenitors with potential application as adjuncts to HSC–based cellular therapy.
Pathways of T‐cell regeneration in mice and humans: implications for bone marrow transplantation and immmunotherapy
Authors: Mackall Crystal L. , Gress Ronald E.
Published: April 2006

Summary: Much of our understanding of the immunobiology of bone marrow transplantation (BMT) has come from studies in young adult mice reconstituted with T‐cell‐depleted bone marrow after lethal irradiation. Recent evidence indicates, however, that the applicability of conclusions drawn from this model to human BMT may be limited. While mice retain essentially normal thymic function well past sexual maturity, humans show significant age‐related declines in thymic function age‐early in life. Therefore, thymic‐deficient mice may provide a more accurate model for study of the immunobiology of BMT T‐cell regeneration in thymic‐deficient mice occurs primarily via antigen‐driven expansion of mature peripheral T cells resulting m limited immune competence due to quantitative deficiencies in T‐cell number and severe restriction in the diversity of the regenerated T‐cell receptor (TCR) repertoire. Similarly, immune reconstitution in adult humans after BMT is marked by quantitative T‐cell deficiencies, especially in the CD4+ subset, and loss of TCR diversity. Taken together, prevailing evidence suggests that thymic function is suboptimal in most BMT recipients, and that thymic‐independent pathways of T‐cell regeneration are generally limited in their ability to restore host immune competence. New strategies to enhance thymic function in man after BMT would hold great therapeutic potential.
Immunological reconstitution following bone marrow transplantation
Authors: Parkman Robertson , Weinberg Kenneth I.
Published: April 2006

Summary: The recipients of hematopoietic stem cell transplants are characterized by an immunodeficiency of varying severity and duration. Their immunoincompetence is due in part to: 1) a lack of sustained transfer of donor immunity, 2) a recapitulation of lymphoid ontogeny, 3) the effects of graft‐versus‐host disease and its therapy, and 4) a reduction in thymic function. Recipients can have delays in the production of naive T lymphocytes following transplantation which result in defects in the production of new antigen‐specific T lymphocytes and an inability to produce antibodies, especially to carbohydrate antigens.
Therapy with cultured T cells: principles revisited
Authors: Cheever Martin A. , Chen Wei
Published: April 2006

Summary: In animals and in humans, T‐cell therapy can cure advanced disseminated leukemia that would otherwise be fatal. The therapeutic effect of immune T cells is quantitative. As the dose of effector T cells is increased, survival is proportionately increased. Therefore, effective T‐cell therapy is predicated on the ability to procure large numbers of immune effector T cells. By using cultured T cells, the number of immune T cells can be increased in vivo substantially above che level achievable by vaccination. The survival of cultured T ceils in vivo is dependent upon both the culture conditions used and the therapeutic regimens employed. Under appropriate conditions, cultured T ceils can proliferate in vivo in response to stimulation by antigen, distribute widely and survive long term to provide effector function and immunologic memory. Given that T cells recognize peptides. the need for immunization with tumor can be circumvented by immunization with peptide. Peptide‐specific T cells and the progeny of single T‐cell clones can provide the necessary cellular functions to eradicate disseminated murine leukemia. The ability of cloned T cells to similarly provide substantial measurable immunity in humans has been validated in clinical trials. By priming with peptides and by using established culture conditions, T‐cell therapy can now be directed against virtually any antigen within the host T‐cell repertoire. The major remaining question to be answered is which proteins and which peptides are the most suitable targets for T‐cell therapy trials.
Adoptive cellular immunotherapy for EBV lymphoproliferative diseases
Authors: Heslop Helen E. , Rooney Cliona M.
Published: April 2006

Summary: Reactivation of EBV (Epstein‐Barr virus) after bone marrow transplantation can result in EBV‐associated lymphoproliferative disease (EBV‐LPD), We have administered donor‐derived EBV‐specific cytotoxic T lymphocytes (CTL) to patients who are at high risk of this complication after receiving a T‐cell‐depleted allograft from a matched unrelated or mismatched related donor. The cells were marked with (he neo GENE U fore infusion so that we could evaluate their persistence and efficacy, CTL infusion produced a virus‐specific immune response to EBV that persisted for up to 2 years. None of the 36 patients who received prophylactic CTLs have developed EBV‐LPD compared with a cumulative risk of 14% in patients who did not receive this treatment. Strong evidence of clinically valuable immune activity conies from 6 of these 36 patients whose pre‐CTL levels of EBV DNA were elevated to a degree strongly predictive of the onset of lymphoma. In each of these cases, the levels returned to baseline after CTL infusion. 2 patients who were treated for clinically evident EBV‐LPD attained prolonged remission after CTL infusion and in situ hybridization and semiquantitative PCR showed that the gene‐marked CTL had selectively accumulated at disease sites, The prophylactic CTL treatment lacked acute adverse effects, whereas 1 patient who received CTLs for bulky established disease developed initial tumor swelling and respiratory obstruction. We conclude that EBV‐specific CTLs are a safe and effective prophylaxis for EBV lymphoma and can also eradicate established disease. This approach is now being extended lo other viruses that produce post‐trans‐plant morbidity and to other EBV‐associated malignancies.
Cytotoxic T‐lymphocyte (CTL) responses against acute or chronic myeloid leukemia
Authors: Falkenburg J.H. Frederik , Smit Willem M. , Willemze Roel
Published: April 2006

Summary: In addition lo chemotherapy and irradiation, in the context of allogeneic stem cell transplantation (SCT), the donor cell‐mediated anti‐leukemic effect can lead to sustained complete remissions, also in cases of a large tumor load. This phenomenon appears to be an immunologically mediated response, possibly due to various effector cell populations. Cytotoxic T‐lymphocyte (CTL) responses against minor histocompatibility antigens with restricted tissue distribution, in particular restricted to some or all hematopoietic cells, may be highly efficient in inducing and‐leukemic responses for adoptive immunotherapy Specific CTL responses against leukemia‐associated antigens may be generated using leukemic cells modified to co‐express costimulatory molecules identical to professional antigens may be used in the context of allogeneic tells Donor derived T cell recognizing such antigens may be used in the context of allogeneic SCT to induce complete and sustained remissions, also in patients with leukemia refractory to chemotherapy. In these to circumstances, the primary objective of allogeneic SCT may be not to diminish the number of malignant cells by the chemotherapy and irradiation as part of the conditioning regimen, but to allow immunotherapy against leukemic cells using donor lymphocyte populations.
Studies in listeriosis show the strong symbiosis between the innate cellular system and the T‐cell response
Authors: Unanue Emil R.
Published: April 2006

Summary: Resistance to infection with Listeria monocytogenes involves a series of cellular interactions, many of which are carried on by cytokines. Macrophages. NK cells and neutrophils participate in early stages of Listeria resistance. The neutrophil is specially important for clearance of the liver phase of listeriosis. Macrophages and NK cells interact by way of IL‐12 and TNF, which induce the NK cell to produce IFN‐γ. IFN‐γ 'S the major macrophage‐activating cytokine. The CB‐I7 SCID mouse shows these cellular interactions restricting the growth of Listeria, without its elimination. CD4 and/or CDS T cells bring about sterilizing immunity, Macrophages influence the lymphocyte response by way of antigen presentation and also by promoting Th1 differentiation, Thus, elimination of Listeria requires a symbiosis between innate immunity and the T‐cell system.
Murine listeriosis as a model of antimicrobial defense
Authors: North Robert J. , Dunn Pamela L. , Conlan J. Wayne
Published: April 2006

Summary: Murine listeriosis was introduced 35 years ago as a model with which to analyze mechanisms of antibacterial defense that are independent of antibodies. Listeria monocytogenes was shown to be an intramacrophage pathogen with capacity to induce the generation of a state of specific immunity in the form of DTH and a macrophage system with enhanced non‐specific bactericidal activity The demonstration that anti‐Listeria immunity and DTH can be passively transferred with T cells was taken to indicate that the T cells responsible for DTH function upregulate the listericidal function of macrophages. This interpretation is contradicted by recent research showing that CDS T cells, rather than CD4 T cells, are responsible for mediating adoptive immunity. However, T‐cell depletion studies show that primary infection can eventually be resolved in the absence of either CDS or CD4 T cells. On the other hand, infection becomes lethal in the absence of neutrophils or NK cells. It is apparent, therefore, that the most important defense against primary listeriosis resides with the functions of neutrophils and NK cells that are mobilized early in infection. Antigen‐specific T cells function at a later time to infection more efficiently. It is apparent that T cells are much more important in defense against secondary infection.
Some macrophages kill Listeria monocytogenes while others do not
Authors: Fleming Sherry D. , Campbell Priscilla A.
Published: April 2006

Summary: It is not known why some macrophages can kill certain microbes, such as the facultative intracellular bacterium Listeria monocytogenes (L. monocytogenes), while other macrophages cannot. Perhaps listericidal activity is a property of macrophages at specific stages of differentiation; maybe the ability to kill this bacterium is regulated by the microenvironment of the cell; or it is possible that other regulatory forces are important. We describe here three characteristics that distinguish macrophages which can kill I. monocytogenes from those which cannot. First, listericidal macrophages must have neither too much nor too little intracellular iron ‐ they must have an intermediate amount. Second, the receptor a macrophage uses to phagocytose L. monocytogenes seems to influence the intracellular fate of this bacterium. And third, macrophages which have cell‐surface interleukin‐10 (IL‐10), a known down regulator of macrophage function, can‐not kill L. monocytogenes. These trails of macrophages and their effects on listericidal activity are reviewed here, and the possibility that these properties might interact to control macrophage bactericidal activity is discussed.
CTL responses to H2‐M3‐restricted Listeria epitopes
Authors: Lenz Laurel L. , Bevan Michael J.
Published: April 2006

Summary: Cytotoxic T cells (CTL) play a critical role in the murine immune response to Listeria monocytogenes (Listeria), Bacterial antigens are presented lo Listeria‐specific CTL by products of both conventional, polymorphic MHC class Ia and non‐polymorphic MHC class Ib alleles. The H2‐M3 class Ib gene product. M3, preferentially presents formylmethionine‐initiating (fMet) peptides derived from the N termini of bacterial and mitochondrial proteins. Thus, M3 signals the presence of bacterial invaders to CTL effectors, Listeria‐encoded fMet peptide epitopes for H2‐M3‐restricted CTL have recently been identified. These and other identified fMet peptides are predominantly comprised of hydrophobic residues and appear lo be cleaved from membrane‐bound proteins. The subcellular location and membrane topology of such proteins may be significant factors in their selection as target antigens for H2‐M3‐restricied CTL. Such rules may prove useful for prediction of candidate fMet peptide epitopes from other bacterial proteins and species. Studies using synthetic fMet peptides to stimulate CTL ex vivo are also discussed, These latter studies indicate that Listeria infection boosts H2‐M3‐restricted CTL responses. However, in contrast to MHC class la‐restricted CTL responses, fMet peptide‐specific CTL are observed in a large proportion of cultures from non immunized, conventionally housed (non‐SPF) mice. The CTL activity in these latter cultures may reflect priming in vivo on cross‐reactive antigens, or may indicate that requirements for priming of H2‐M3‐restricted CTL are less stringent than for class Ia‐restricted responses.
MHC class I antigen processing of Listeria monocytogenes proteins: implications for dominant and subdominant CTL responses
Authors: Pamer Eric G. , Sijts Alice J.A.M. , Villanueva Merceditas S. , Busch Dirk H. , Vijh Sujata
Published: April 2006

Summary: Listeria monocytogenes (L. monocytogenes) secretes proteins associated with its virulence into the cytosol of infected cells. These secreted proteins are degraded by host cell proteasomes and processed into peptides that are bound by MHC class I molecules in the endoplasmic reticulum. We have found that the MHC class I antigen‐processing pathway is very efficient at generating the epitopes that are presented to cytolytic T lymphocytes (CTL). Depending on which antigen is investigated, from 3 to 30 % of degraded antigens are processed into nonamer peptides that are bound by MHC class I molecules. Surprisingly, neither the efficiency of epitope generation nor the absolute number of epitopes per infected cell determines the magnitude of the in vivo CTL response. One of the least prevalent epitopes, derived from an antigen that is virtually undetectable in infected cells, primes the immunodominant CTL response in L. monocytogenes‐infected mice. Our studies suggest that immunodominant and subdominant T‐cell responses cannot be predicted by the prevalence of antigens or epitopes alone, and that additional factors, yet to be determined, are involved.
Complement receptors in HIV infection
Authors: Speth Cornelia , Kacani Laco , Dierich Manfred R
Published: April 2006

The complement system plays an important role in the antimicrobial defense of the organism. Its components recognize a large variety of pathogens and target them for destruction, either directly by formation of a membrane attack complex or indirectly by recruiting phagocytic cells. In addition, it has several functions in cell activation, clearance of immune complexes, control of inflammatory reactions, chemotaxis and autoimmunity For mediation of all these tasks of the complement system, complement receptor molecules on the cell surface play a key role. Current knowledge on structure, function, signal transduction and associated molecules is briefly summarized here.

The role of complement receptors for human immunodeficiency virus (HIV)‐associated pathogenesis is ambiguous and varies depending on cell type. On the one hand, complement receptors support the infected host to manage HIV infection and to defend itself, at least partially, against viral spreading throughout the organism. Such complement receptor‐mediated supporting mechanisms are activation of immune cells and lysis of viral particles and infected host cells. On the other hand, HIV employs complement receptors to intrude more easily into various cell types, to become localized into lymph follicles and to activate viral replication in latently infected cells. This review summarizes the complex interaction of virus and complement receptors in HIV infection for different cell types.
Complement and immunity to viruses
Authors: Lachmann Peter J. , Davies Alexandra
Published: April 2006

Complement is one of the first lines of host defence to be faced and countered by viruses as they struggle to establish an infection. As an important arm of the humoral immune response, the complement system is immediately ready to target and eliminate virus particles and to interact with the surface of virus‐infected cells to mark them for destruction by other branches of the immune response. Nevertheless, some viruses are still very successful human pathogens. This article will discuss the role of complement in antiviral immunity, the mechanisms by which complement may be activated by viruses or virus‐infected cells, and explore some of the strategies which viruses have evolved to subvert the immune response, including mechanisms by which complement activation may be prevented or aborted.
αβ and γδ T‐cell networks and their roles in natural resistance to viral infections
Authors: Welsh Raymond M. , Lin Meei‐Yun , Lohman Barbara L. , Varga Steven M. , Zarozinski Christopher C. , Selin Liisa K.
Published: April 2006

Both αβ and γδ T‐cell populations and natural killer (NK) cells include cytotoxic, interferon (IFN)‐γ‐producing lymphocytes that actively respond to viral infections. We show here that all three populations can provide “natural resistance“ of viruses very early in infection and describe how the T‐tell populations are modulated TO provide this function. γδ T cells were shown to play a role in controlling vaccinia virus (VV) infections, as VV grew to much higher titers in γδ T‐cell knockout mice than in normal mice 3–4 days post‐infection. Our studies of the of T‐cell responses to viruses revealed an interactive network of T cells that is modulated substantially during systemic infections. There is an induction phase associated with a massive virus‐specific CD8 T‐cell response, an apoptosis phase during which the T cells become sensitized to activation‐induced ceil death (AICD). a silencing phase, during which the T‐cell number and activation state is reduced, and. finally, a memory phase associated with the very stable preservation of virus‐specific memory cytotoxic T‐lymphocyte precursors (pCTL). Infection of mice immune to one‐H US with a heterologous virus leads to a selective expansion of memory CTL cross‐reacting between the two viruses, but, after homeostasis is again established, there is a quantitative reduction and quantitative alteration of memory to the first virus. Our results suggest that memory of T cells cross‐reactive between heterologous viruses mediate both immunopathology and protective immunity at early stages of the second viruses infection. Thus, memory αβ T cells can, like γδ T cells and NK cells, provide natural immunity to viral infections.
Role of the B‐cell response in recovery of mice from primary influenza virus infection
Authors: Gerhard Walter , Mozdzanowska Krystyna , Furchner Michelle , Washko George , Maiese Krista
Published: April 2006

Recovery from influenza virus infection has long been known to require an intact T‐cell compartment. More recent studies revealed that CD8 and CD4Tcells can promote recovery through independent mechanisms. The CD4 T‐cell‐dependent recovery process appears to operate primarily through promotion of the T‐dependent antibody response as B‐cell‐deficient μMT mice cannot recover from infection if they have been depleted of CDS T cells. The potential therapeutic activity of the B‐cell response was further studied by transfer of antibodies into infected SCID mice. At the dose of 200 μg/mouse. most antibodies (of IgG2a isotype) to the viral transmembrane protein HA cured the infection, while those to the transmembrane proteins NA and M2 suppressed virus titers in the lung but failed to clear the infection. The ability of passive antibody to resolve the‐infection was closely related to its prophylactic activity, suggesting that neutralization of progeny virus (VN) played an important role in the process of virus clearance in vivo, while reaction of antibodies with infected host cells contributed to but was insufficient, on its own for cure. HA‐specific antibodies of IgM and IgA isotypes were therapeutically ineffective against pulmonary infection, presumably because of a preferential delivery into the upper respiratory tract, while IgG exhibited highest activity against pulmonary and minimal activity against nasal infection. B cells appear to be of similar importance for recovery from primary infection as CDS T cells.
Cytokines and immunity to viral infections
Authors: Ramshaw Ian A. , Ramsay Alistair J. , Karupiah Gunasegaran , Rolph Michael S. , Mahalingam Surendran , Ruby Janet C.
Published: April 2006

In this review, we discuss two broad approaches we have taken to study the role of cytokines and chemokines in antiviral immunity. Firstly, recombinant vaccinia viruses were engineered to exit encoding cytokines and chemokines of interest. Potent antiviral activity was mediated by many of these encoded factors, including IL‐2, IL12. IFN‐γ. TNF‐α. CD40L. Mig and Crg‐2, In some cases, liosi defense mechanisms were induced (IL‐2, IL‐t2. Mig and Crg‐2), whilst for others, a direct antiviral effect was demonstrated (IFN‐γ. TNF‐α and CD40L), In sharp contrast, vector‐directed expression of IL 4, a type 2 factor, greatly increased virus virulence, due 10 a downregulation of host type 1 immune responses. Our second experimental approach involved the use of strains of mice deficient for the production of particular cytokines or their receptors, often in combination with our engineered viruses. Mice deficient in either IFN‐γ, IFN‐γR, IFN‐α/βR, TNFFRs, CD40 or IL‐6 were, in general, highly susceptible to poxvirus infection. Surprisingly, not only the TNFR1, but also the TNFR2, was able to mediate the antiviral effects of TNF‐α in viv, whilst the antiviral activity observed following CD40‐CD40L interaction is a newly defined function which may involve apoptosis of infected cells. Through the use of perforin‐deficient mice, we were able to demonstrate a requirement for this molecule in the clearance of some viruses. such as ectromelia virus, whilst for others, such as vaccinia virus, perforin was less important but IFN‐γ was essential.
Vaccinia virus immune evasion
Authors: Smith Geoffrey L. , Symons Julian A. , Khanna Anu , Vanderplasschen Alain , Alcami Antonio
Published: April 2006

Vaccinia virus and other poxviruses express a wide variety of proteins which are nonessential for virus replication in culture but help the virus to evade the host response to infection. Examples include proteins which oppose apoptosis. Synthesise steroids, capture chemokines, counteract complement, interfere with interferon and intercept interleukins. This review provides an overview of such proteins, with an emphasis on work from our laboratory, and illustrates how the study of these proteins can increase our understanding of virus pathogenesis, the function of the immune system and how to make safer and more immunogenic poxvirus‐based vaccines.
The infection of mouse by Theiler's virus: from genetics to immunology
Authors: Monteyne Philippe , Bureau Jean‐Francois , Brahic Michel
Published: April 2006

Theiler's virus is a picornavirus of mouse which Closes U ac UK encephalomyelitis followed by a persistent infection of the white matter o f the spinal cord with chronic inflammation and demyelination. This Ute disease is studied as a model for multiple sclerosis. Inbred strains of mice differ in their susceptibility to persistent infection and demyelination, Resistant strains clear the infection after the acute encephalomyelitis. This observation is the basis of genetic studies which we used as a thread for this review. The H‐2D locus has a major effect on susceptibility. The H‐2Db gene is involved in a fast and intense CTL response which confers resistance. The Tcrb locus is also implicated, although there is no proof that the susceptibility gene in this region co des for the T‐cell receptor. A complete screen of the genome uncovered the role of the Ing locus and led to the demonstration that IFN‐γ limits viral spread in the white matter. The roles of NK cells and B cells in limiting the infection are discussed. CD4+ T cells participate both in protection against the infection and in demyelination. Finally, the effect of non‐immune factors in resistance is illustrated by mice with mutations in the MBP or PLP gene.