PubMed Health⌕ Search

Biomedical subjects

H N Claman

Publications and source records attributed to H N Claman.

At least 19 recordsLinked to original sources
PubMed1991

Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin".

We studied the immunohistochemistry of the skin of scleroderma patients to determine the differences (if any) between clinically "affected" and "nonaffected" areas. We examined paired skin biopsy samples from clinically involved forearm skin ("affected") and clinically uninvolved proximal skin ("nonaffected") taken from 19 patients with diffuse scleroderma and from 15 normal control subjects. We stained the sections with antibodies to endothelial leukocyte-adherence molecule type 1 (ELAM-1; to detect endothelial activation) and to procollagen-1 (PC-1; to detect newly formed, unprocessed collagen). There was increased expression of ELAM-1 and PC-1 in sclerodermatous skin as compared with the controls, but there was no difference between clinically affected and nonaffected skin samples. In 10 of 11 patients whose condition was getting worse, endothelial and fibroblast activation preceded fibrosis. Endothelial and fibroblast activation are more widespread in the skin of scleroderma patients than is evident by inspection on physical examination. What appears to be "normal" skin in diffuse scleroderma is already pathologic, as shown by abnormal endothelial activation and procollagen production.

Adult↗
PubMed1991

Morphological evidence for chronic mast cell activation after prolonged exposure with supernatants from chronic graft-versus-host splenocytes.

Chronic graft-vs.-host disease (cGVHD) includes a syndrome of inflammatory and fibrotic changes in some respects resembling scleroderma. In the present study we have quantitated the number of peritoneal mast cells (MC) in mice with cGVHD induced across minor histocompatibility barriers. MC were evaluated by staining with toluidine blue. The number of MC decreased significantly (by 25%) at the onset of the cGVHD fibrosis (day 12). Around day 35, MC were virtually undetectable, and started to reappear on day 130. Upon clinical recovery (day 200) a dramatic increase in MC numbers was found (about 8-fold). In addition, we evaluated by electron microscopy the morphology of peritoneal MC, obtained from normal mice and rats, that had been co-cultured on 3T3 fibroblast monolayer in the presence of splenocyte supernatants from mice with cGVHD or from control mice. After 6-8 days of continuous incubation with the cGVHD splenocyte supernatant, MC appeared to be activated, since they displayed an array of heterogenous granules. Few of the granules were dense; many were swollen and pale. Rare granule extrusion was evident. This would indicate that MC underwent a slow activation process due to a factor(s) present in the cGVHD supernatant, different from the classical acute anaphylactic activation.

Animals↗
PubMed1990

Histamine release from mouse and rat mast cells cultured with supernatants from chronic murine graft-vs-host splenocytes.

There is growing interest in studying pathways of mast cell activation. In a mouse model of chronic graft-vs-host disease (cGVHD) extensive mast cell activation and degranulation occurs in vivo coincident with the development of dermal fibrosis. An interesting feature of this model is that the mast cell reaction is slow to develop, occurring over a period of weeks and waning by 300 days. The aim of our work was to investigate the effects of supernatants from splenocytes of such cGVHD mice (cGVHD sups) on mouse and rat peritoneal mast cells cocultured with 3T3 skin fibroblasts. We found that cGVHD sups are able to release histamine from both mouse and rat cultured mast cells in a slow fashion. Histamine release became evident only after 5-8 days of coculture of the mast cells with the cGVHD supernatants and thereafter decreased to basal levels. Mast cell activation due to cGVHD supernatants was a noncytotoxic event as demonstrated by mast cell counts in the cocultures and by the ability of mast cells to exclude trypan blue. Mast cells that had been activated by incubation with the cGVHD sups were as responsive to stimulation with either anti-IgE antibodies or compound 48/80 as were mast cells incubated with control sups. Supernatants from mice early in GVHD (Days 11-28) were most active in promoting histamine release. Supernatants from spleens of mice which had GVHD for 290 days and where the mast cells had returned to full granulation in vivo were inactive. This is the first in vitro study demonstrating slow mast cell histamine release instituted by other cells, namely the splenocytes of cGVHD mice.

Animals↗
PubMed1990

Dermal mast cell degranulation in systemic sclerosis.

Paired biopsy samples from involved and uninvolved skin were obtained from 19 patients with generalized scleroderma (11 with early, progressive disease and 8 with late, improving disease). Skin biopsy samples were double stained for mast cell granules and for mast cell membrane. The number of mast cells was increased in patients with systemic sclerosis (SSc), in both involved and uninvolved skin and in both early and late disease. There was an increase in the number of degranulated mast cells in the involved skin of patients with both early and late disease and in the not-yet-involved skin of patients with early disease; however, there was no increase in the number of degranulated mast cells in areas of previously involved but now normal skin of patients with late disease. Increases in mast cell number and degranulation precede clinically apparent dermal fibrosis in SSc. These observations and the absence of mast cell degranulation in regressing skin suggest a participatory role of the mast cell in the clinical progression of skin changes in SSc.

Adult↗
PubMed1990

IL-3, IL-4, and IL-6 enhance IFN-gamma-dependent bone marrow natural suppressor activity.

The ability of murine bone marrow (BM) natural suppressor (NS) cells to suppress a Con A proliferation assay was greatly enhanced by supernatant obtained from the T cell hybridoma D9C1.12.17. Of the lymphokines produced by this hybridoma, three were found to enhance suppression: interleukin-3 (IL-3), IL-4, and IL-6. These molecules enhanced suppression of both unirradiated and irradiated (2000 R) BM cells indicating that augmented suppression was not just due to proliferation of NS cells. The ability of all three of the lymphokines to enhance BM suppression could be blocked by anti-interferon-gamma (IFN-gamma) antibody. These results indicate that (1) NS cell activity is not radiosensitive and (2) that two signals may be required for maximal NS cell suppression, one being a lymphokine-mediated signal and the other IFN-gamma.

Animals↗
PubMed1990

Immunoglobulin dysregulation in murine graft-vs-host disease: a hyper-IgE syndrome.

Immunoglobulin production, particularly IgE, is known to be dysregulated in graft-vs-host disease (GVHD). We examined serum levels of the highly T-dependent Ig isotypes, IgE, IgG1, and IgG2a, in two different mouse models of GVHD. GVHD across minor histocompatibility barriers is produced by injection of B10.D2 spleen cells into 600 rad irradiated BALB/c hosts. Both strains are H2d and mls b, but differ at the minor histocompatibility antigens. As GVHD progresses there is a rapid rise in serum IgE (300-fold) and IgG1 (2.5-fold) with a peak at Day 14. Concomitantly, IgG2a falls. Serum immunoglobulin levels return to normal by 11 weeks. The rise in IgE is abolished by increased (900 rad) recipient irradiation, suggesting that host-derived factors are important. GVHD across major histocompatibility barriers is produced by injection of DBA/2 spleen cells into unirradiated or 600 rad irradiated (B6 x DBA/2)F1 hosts. Only in the irradiated recipients is there severe Ig dysregulation. In this situation there is a 100-fold rise in IgE, and 5- to 10-fold rises in IgG1 and IgG2a. While the results in GVHD across minor barriers suggest stimulation of T helper cells secreting IL-4, the increase in IgE, IgG1, and IgG2a levels in GVHD across major barriers suggests activation of IL-4 and IFN-gamma-secreting T cells. These results indicate that different mechanisms may be operating in these two models of GVH. Murine GVHD can serve as a model for studying dysgammaglobulinemias in general and for hyper-IgE formation in particular.

Animals↗
PubMed1990

Mast cells and fibrosis. The relevance to scleroderma.

Mast cells are being recognized as important constituents in fibrotic processes. This article reviews the evidence for increased mast cell numbers and/or function in a variety of fibrotic conditions. Increased mast cell numbers and activity are seen in chronic murine graft-versus-host disease (a model for scleroderma) and in active scleroderma itself. An integrated schema for scleroderma is presented, emphasizing the interactions among mast cells, endothelial cells, and fibroblasts mediated by heparin and heparin-binding growth factors.

Animals↗
PubMed1989

On scleroderma. Mast cells, endothelial cells, and fibroblasts.

An integrated view of the pathogenesis of scleroderma should include vascular, immunologic, and fibrotic processes. This review introduces the mast cell into this picture, emphasizing recent knowledge gained from a study of experimental chronic graft-vs-host disease and scleroderma itself. In both of these situations, increased mast cell activity occurs. A link between the activation of both endothelial cells and fibroblasts may be provided by the family of heparin-binding growth factors. These cytokines are produced by many cells and are bound, protected, and enhanced by heparin, which may be provided by the activated mast cells. These and other growth factors may be responsible for endothelial proliferation and excess collagen production by fibroblasts. This enlarged schema should provide additional points for therapeutic intervention in scleroderma.

Cell Differentiation↗
PubMed1989

Hepatic homing of mononuclear inflammatory cells isolated during murine chronic graft-vs-host disease.

Liver injury in murine chronic graft-vs-host disease (CGVHD) to minor histocompatibility Ag, B10.D2----BALB/c (600 rad), is characterized by mononuclear cell inflammation and necrosis of interlobular bile ducts. Bile duct destruction in this model is similar to that which occurs in human CGVHD, late liver transplant rejection, and primary biliary cirrhosis. This model provides a unique opportunity to isolate mononuclear inflammatory cells from the liver during CGVHD, study their functions, and investigate the immunologic mechanisms responsible for bile duct destruction. In the present study, we compared the in vivo organ homing of mononuclear inflammatory cells (MC) isolated from the liver and spleen during the course of CGVHD. MC isolated from the liver showed a progressive increase in homing to the livers of BALB/c mice from day 7 through 42. In contrast, the hepatic homing of MC isolated from the spleen peaked at day 21 and subsequently declined. CGVHD spleen MC showed a progressive increase in homing to the spleen of BALB/c mice whereas CGVHD liver MC showed no change over time. Homing to other organs was negligible. The hepatic and splenic homing of MC isolated during CGVHD was significantly greater in BALB/c (host) mice than in B10.D2 (donor) mice. Autoradiography was used to determine the intrahepatic sites at which CGVHD liver MC accumulate after i.v. injection into BALB/c mice. The results indicated that MC isolated from the liver when bile duct inflammation is most intense accumulate preferentially in hepatic portal spaces in close proximity to interlobular bile ducts. These results suggest that hepatic homing by CGVHD liver MC is specific for minor histocompatibility Ag expressed on host biliary epithelial cells. These data support the hypothesis that bile duct destruction in murine CGVHD is mediated by MC that are sensitized to minor histocompatibility Ag expressed by host biliary epithelial cells.

Animals↗
PubMed1989

Murine natural suppressor cells in the newborn, in bone marrow, and after cyclophosphamide. Genetic variations and dependence on IFN-gamma.

Natural suppressor (NS) cells are potent, Ag nonspecific, MHC-unrestricted inhibitors of immune responses. Murine NS activity is found in several situations, including adult bone marrow (BM) and neonatal/newborn spleen, and spleen following total lymphoid irradiation, after BM transplantation and after cyclophosphamide (CY) treatment. Using three of these situations (adult BM, newborn spleen, and spleen after CY treatment), the strain distribution of NS cell activity was assessed. A wide variation in potency is seen in both naturally occurring (adult BM and newborn spleen) and induced (after CY treatment) NS cell activity. Up to 10-fold differences in NS activity are seen between high and low NS strains. This reflects an intrinsic genetic variation between mouse strains in both naturally occurring and CY-induced NS cell activity. Thus, a strain with high NS activity at birth, has high NS activity in its BM as an adult and in its spleen after CY treatment. Of the strains tested, B10.D2 has the highest NS cell activity while BALB/c has the lowest, and the F1 between these two strains is intermediate in NS activity. Finally, the NS cell activity from all strains tested required IFN-gamma for expression of its inhibitory activity.

Aging↗
PubMed1989

Mast cell changes in a case of rapidly progressive scleroderma-ultrastructural analysis.

A 63-year-old woman had rapidly progressive scleroderma and died 4 months after the clinical appearance of her illness. Extreme itching of the affected skin was prominent. Electron microscopic study of the clinically uninvolved skin showed mainly normal mast cells. Mast cells in clinically involved skin showed a wide morphologic spectrum including evidence of cellular activation. There was an increased amount of cytoplasm occupied by polysomes and mitochondria and less cytoplasm occupied by granules. Most granules were pale and swollen, suggesting active degranulation. In some cases it was difficult to distinguish a hyperactive mast cell with only a few granules remaining from a fibroblast which had acquired granules by transgranulation. This case illustrates the active participation of mast cells in acute scleroderma.

Biopsy↗
PubMed1989

Ultrastructural evidence for mast cell activation in a case of neurofibromatosis.

Neurofibromas contain fibroblasts and many mast cells, and recent hypotheses have linked fibrous tissue growth to activated mast cells. We describe the ultrastructure of mast cells and fibroblasts in a case of neurofibromatosis. Mast cells were numerous and showed extensive signs of activation. Mast cells were often intimately associated with fibroblasts, and mast cell granules could be seen inside fibroblasts ('transgranulation'). The fibroblasts were also activated. These results suggest that interactions between mast cells and fibroblasts may be important in the prominent collagen production that takes place in these tumors.

Adult↗