Ames hypopituitary dwarf mice demonstrate imbalanced myelopoiesis between bone marrow and spleen.

Ames hypopituitary dwarf mice are deficient in growth hormone, thyroid-stimulating hormone, and prolactin. The phenotype of these mice demonstrates irregularities in the immune system with skewing of the normal cytokine milieu towards a more anti-inflammatory environment. However, the hematopoietic stem and progenitor cell composition of the bone marrow (BM) and spleen in Ames dwarf mice has not been well characterized. We found that there was a significant decrease in overall cell count when comparing the BM and spleen of 4-5 month old dwarf mice to their littermate controls. Upon adjusting counts to differences in body weight between the dwarf and control mice, the number of granulocyte-macrophage progenitors, confirmed by immunophenotyping and colony-formation assay was increased in the BM. In contrast, the numbers of all myeloid progenitor populations in the spleen were greatly reduced, as confirmed by colony-formation assays. This suggests that there is a shift of myelopoiesis from the spleen to the BM of Ames dwarf mice; however, this shift does not appear to involve erythropoiesis. The reasons for this unusual shift in spleen to marrow hematopoiesis in Ames dwarf mice are yet to be determined but may relate to the decreased hormone levels in these mice.

An association of hypochondroplasia and immune deficiency.

A 4-year-old boy with hypochondroplasia was admitted to our clinic with complaints of bronchopneumonia. He also had immune deficiency characterized by low CD3, CD4 T-lymphocyte subsets and a low level of serum immunoglobulin A (IgA). The diagnosis of hypochondroplasia was made on clinical, radiological, and laboratory findings by the pediatric endocrinology department. The focus of our study is hypochondroplasia associated with immune deficiency which was unpublished in English medical literature previously.

Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome.

AIMS: To obtain an understanding of the etiology of proportional dwarfism and endocrinopathies of Bloom's syndrome BS. METHODS: Admission for 5-day periods to an NIH-supported Clinical Research Center of a randomly selected population of persons with BS (n = 11; mean age 11.5 years, range 9 months to 28.5 years) for clinical and genetic history-taking, physical examination, and endocrinological, gastroenterological and immunological testing. RESULTS: An oral glucose tolerance test was performed in all participants. Impaired glucose tolerance was present in 4 individuals, insulin resistance was observed in 6 individuals, and previously unrecognized diabetes was found in 1. Growth hormone provocation was normal in the 10 individuals tested. Overnight frequent GH sampling was suggestive of neurosecretory dysfunction in 3. Compensated hypothyroidism was found in 2 participants. Lipid profile abnormalities were present in 5 of 10 individuals. Low immunoglobulin concentrations (IgG and/or IgM) were seen in all tested. Intestinal absorption by D-xylose and/or fecal fat measurement was normal in all individuals tested as well. CONCLUSION: Altered carbohydrate metabolism is very common in BS, and is present from childhood. BS dwarfism is not related to growth hormone deficiency or malabsorption. The basis for the growth restriction in BS remains to be elucidated.

[Schimke immuno-osseous dysplasia. A pediatric disease reaches adulthood]. / Schimke-immunoossäre Dysplasie. Eine pädiatrische Erkrankung wird erwachsen.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder caused by mutations of the SMARCAL 1 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). CLINICAL FEATURES: Main clinical features are: disproportional growth deficiency due to spondyloepiphyseal dysplasia, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Patients with severe SIOD have life-limiting complications like cerebral ischemia due to vaso-occlusive processes. Only a few patients reached adulthood. CASE REPORTS: The clinical course of four adult SIOD patients is presented. CONCLUSION: Even patients with severe SIOD can reach adulthood. Therefore, doctors working in the field of internal medicine and family doctors should be familiar with the clinical picture of SIOD.

Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis.

Increased plasma IGF-1 has consistently been associated with a variety of human cancers, whereas reduced levels of IGF-1 are associated with increased lifespan in other species. However, the aforementioned relationships are correlational or are derived from animal models that are not specific for growth hormone/IGF-1 excess or deficiency. This study was designed to assess the effects of physiological changes in growth hormone and IGF-1 expression on dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. At 50 days of age, female heterozygous (dw/+) and growth hormone deficient dwarf (dw/dw) rats of the Lewis strain received a single dose of DMBA (80 micro g/g of body weight) via oral gavage. Animals were assigned to one of four experimental groups: a) heterozygous animals (normal size), b) dwarf animals administered vehicle, c) dwarf animals administered low levels of porcine growth hormone (50 micro g twice daily), and d) dwarf animals administered high levels of porcine growth hormone (200 micro g twice daily). At study termination, heterozygous animals exhibited a 70% incidence of mammary tumors, whereas no tumors were observed in saline-treated dwarf animals. Administration of either 100 micro g or 400 micro g growth hormone/day resulted in a dose dependent increase in incidence of mammary tumors (83 and 100%, respectively). Furthermore, heterozygous animals exhibited 1.5 +/- 0.25 tumors per tumor-bearing animal, whereas dwarf animals administered 100 micro g and 400 micro g growth hormone per day had 1.9 +/- 0.63 and 3.4 +/- 0.83 tumors per animal, respectively. The present study demonstrates that DMBA-induced carcinogenesis is dependent on critical plasma levels of growth hormone and IGF-1, and that growth hormone/IGF-1 deficient animals are resistant to DMBA-induced carcinogenesis.

Encapsulation for somatic gene therapy.

With the human genome project approaching its completion date of 2005, gene-based technology will play an increasingly important role in health-care delivery. Non-autologous somatic gene therapy is a novel application in which non-autologous cell lines engineered to secrete a recombinant protein are enclosed within immunoisolation devices and implanted into all patients requiring the same product for therapy. The development of this technology requires a multi-disciplinary effort towards optimization of the biomaterial used to manufacture the implantable devices and selection of the appropriate cell lines for enclosure. The efficacy of this technology is illustrated in the treatment of dwarfism and lysosomal storage disease in murine models. The potential of a safe and cost-effective gene-based delivery method should have wide applications in treating both classical genetic disorders and non-Mendelian diseases.

Cartilage-hair hypoplasia syndrome: increased apoptosis of T lymphocytes is associated with altered expression of Fas (CD95), FasL (CD95L), IAP, Bax, and Bcl2.

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive short-limbed dwarfism associated with thin and sparse hair and cell mediated or combined immunodeficiency. However, the basis of immune deficiency in CHH is unclear. In this study, we investigated a role of apoptosis in immunodeficiency in a patient with CHH. An increased apoptosis of both CD4+ and CD8+ T cells, as determined by TUNEL assay, was observed in CHH compared to an age-matched healthy dwarf control. Increased apoptosis in CHH was associated with increased expression of Fas (CD95), CD95L, and Bax and decreased expression of Bcl-2 and inhibitor of apoptosis protein (IAP) compared to the control. These data suggest that lymphopenia and immunodeficiency in CHH may be, at least in part, due to increased apoptosis of T cells, possibly through the Fas/ FasL signaling pathway.

Radiographic and morphologic findings in a previously undescribed type of mesomelic dysplasia resembling atelosteogenesis type II.

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport.

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice.

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

Cerebral complications in Schimke immuno-osseous dysplasia.

UNLABELLED: Schimke immuno-osseous dysplasia is a multisystem disorder consisting of spondylo-epiphysial dysplasia, progressive renal insufficiency due to focal segmental glomerulosclerosis, and immunodeficiency. Cerebrovascular complications have only been described in five patients. Here we report a patient with prominent neurological symptoms most likely caused by transient ischaemic attacks. CONCLUSION: Neurological symptoms consisted of repeated brief spells of hemiparaesthesia, motoric aphasia and diplopia. MRI studies of the CNS revealed progressive white matter lesions. Morphological changes as well as neurological deficits are compatible with cerebral ischaemia.

Defective B cell development in Snell dwarf (dw/dw) mice can be corrected by thyroxine treatment.

Snell dwarf (dw/dw) mice are deficient in anterior pituitary hormones due to a mutation in the gene encoding the Pit-1 transcription factor. Bone marrow B cell development is also suppressed in the mice, providing circumstantial evidence that one or more anterior pituitary-derived products, or factors induced by them, are required for normal B lymphopoiesis. However, concluding that this is the case is dependent on showing that hormonal treatment of dwarf mice reverses their B cell defects. dw/dw mice were treated with growth hormone (GH), insulin-like growth factor-I (IGF-I), or thyroxine in an attempt to restore bone marrow B lymphopoiesis. GH and IGF-I increased the number of B lineage cells in the bone marrow and spleen but did not restore the frequency of bone marrow pre-B cells to normal. However, bone marrow cellularity in thyroxine-treated dw/dw mice was comparable to that in control animals, and both the frequency and absolute number of B lineage cells had increased to normal or even above normal. Taken together, these data indicate that endocrine factors, especially those regulated by the hypothalamic-pituitary-thyroid axis, are potent B lymphopoietic factors.

Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia.

UNLABELLED: We diagnosed cartilage-hair hypoplasia (CHH) in a female child with prenatal-onset short stature, metaphyseal chondrodysplasia, and severe combined immunodeficiency leading to recurrent, severe respiratory tract infections. The patient required several hospital admissions during her 1st year of life and failed to thrive in spite of antimicrobial therapy and hypercaloric nutrition. Bone marrow transplantation (BMT) from an HLA-identical sister was performed at age 16 months after conditioning with busulphan and cyclophosphamide, using 9 x 10(8) nucleated bone marrow cells/kg body weight. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. The post-transplantation period was uneventful. She developed full and sustained chimerism as demonstrated by DNA analysis of granulocytes and mononucleated cells on days 44, 69 and 455 post BMT. Cellular immunity was completely reconstituted at 4 months, humoral immunity at 15 months post BMT. The patient is alive and well 24 months post BMT without medication, but the radiological osseous changes persist, and longitudinal growth remains markedly below the 10th percentile for CHH standards; her height at age 3 years 4 months is 66 cm. CONCLUSION: In this patient with unusually severe CHH, bone-marrow transplantation has fully corrected the immune deficiency but has had no influence on the course of the chondrodysplasia.

Age-related effects of ectopic pituitary transplants on the activation of Ames dwarf mouse lymphocytes in vitro.

Prolactin (PRL), one of the anterior pituitary hormones, has been implicated in the development and maintenance of immune system function. The following experiments were conducted to evaluate age-related effects of PRL on immune system activity in a PRL-deficient mouse model, the Ames dwarf. Two- and ten-month-old dwarf and phenotypically normal male mice were used. Six dwarf mice from each age group received a surgically implanted pituitary (under the kidney capsule) from a normal donor female mouse. Six different dwarfs were similarly operated but had no pituitary graft inserted and will be referred to as sham-operated dwarfs. Three weeks following surgery, spleens were removed from the dwarfs and age-matched normal mice and splenocytes isolated. The two age groups will subsequently be referred to as "3-month-old" and "11-month-old", respectively, The splenocytes were used in mitogen-induced (concanavalin A (Con A); phytohemagglutinin (PHA); lipopolysaccharide (LPS)) proliferation assays, and histopaque isolated lymphocytes were used for T cell surface marker determination. Pituitary grafting increased body weights of dwarf mice although the weights were less than control mice independent of age. A similar pattern was observed for total number of splenocytes per spleen. In young animals, the relative number of splenocytes per gram of body weight increased in pituitary grafted dwarfs reaching values of control mice, whereas much smaller differences were observed in older animals. The relative percentage of CD4+ cells was reduced (P<0.01) in 3-month-old pituitary-grafted mice, compared with sham-operated dwarf mice, while no differences were observed between sham- operated dwarf and normal mice. Pituitary grafting did not affect the numbers of CD8+ cells. In 11-month-old animals, the relative percentages of CD4+ and CD8+ cells were greater (P<0.05) in sham-operated dwarf than in normal mice but not affected by pituitary grafting. At 3 months of age, proliferation of splenocytes in response to Con A was increased (P<0.05) in sham-operated dwarfs and reduced (P<0.05) in pituitary-grafted dwarfs compared with normal mice. In contrast, PHA stimulation of splenocytes was decreased (P<0.05) in sham-operated compared with normal, and was still lower in mice receiving an ectopic pituitary. Substantially different responses were obtained in 11-month-old animals. In response to Con A, splenocytes from sham-operated dwarfs exhibited a reduced (P<0.05) proliferative capacity as compared with normals, and proliferation was increased in pituitary-grafted as compared with sham-operated dwarfs. In the presence of PHA, the proliferative capacity of splenocytes was greater (P<0.05) in sham-operated dwarfs as compared to normals and pituitary grafting normalized this parameter. These results demonstrate differential effects of PRL deficiency (sham-operated dwarfs versus normal) and of PRL replacement (pituitary-grafted versus sham-operated) in young as compared with old dwarf mice on immune system activation.

Evidence for suppression of immune function by insulin-like growth factor-1 in dwarf rats in vivo.

These studies were undertaken to investigate the effects of increasing or decreasing IGF-1 levels on aspects of immune function in rats. Female dwarf rats were treated with recombinant human IGF-1 or with a potent sheep anti-IGF-serum. Body weight, thymus weight and spleen weight increased with IGF-1 treatment (p < 0.001), while there was no effect of anti-IGF-1 treatment when compared with the appropriate normal sheep serum (NSS) treated controls. IGF-1 treatment significantly decreased WBC and RBC counts, but increased the ratio of CD4+:CD8+ T-cells. Anti-IGF-1 serum had no effect on these parameters compared with NSS. However anti-IGF-1 was associated with increased T-cell numbers, decreased natural killer cells, and enhancement of the animals' ability to produce specific IgG in response to injection of keyhole limpet haemocyanin (KLH). These results indicate that IGF-1 may suppress immune function although increasing the size of immune organs such as spleen.

Growth hormone alters lymphocyte sub-populations and antibody production in dwarf rats in vivo.

Female dwarf rats at different ages were treated with recombinant porcine GH or with a potent sheep anti-rat GH serum. Body weight and spleen weight increased with GH and decreased with anti-GH treatment (p < 0.001). Neither GH nor anti-GH treatment resulted in a change in circulating WBCs, but GH decreased, while anti-GH increased, RBC counts (p < 0.001). Similarly, GH treatment tended to decrease the ratio of CD4+:CD8+ T-cells while anti-GH increased (p < 0.05) the ratio. Anti-GH treatment also enhanced the animals' ability to produce specific IgG in response to KLH injection. These results indicate that GH may have a physiological role in suppressing humoral immune function but may enhance cell-mediated immunity.

[Atopic skeletal retardation as a possible cause for short stature and thoracic deformity in children with asthma]. / Die atopische Skelettretardierung als eine mögliche Ursache für Kleinwuchs und Brustkorbdeformierung asthmakranker Kinder.

Deformities of the chest occur not only in asthmatics suffering from severe attacks, but also in those having a mild form of the disease. It also occurs in children with atopic dermatitis and in members of atopic families without concomitant bronchial asthma. This observation and the fact that asthmatic children tend towards hyposomia, has prompted auxological investigations of asthmatic children. It was of interest to see whether asthma itself or the atopic disposition is responsible for disturbances of growth and development. The investigation was carried out as a cross-sectional study involving 173 asthmatic boys aged 1 1/2-18 years. The programme included among other things age, bone age, bone maturity difference (BMD: difference age minus bone age) height, type and severity of asthma (measured by means of scope of therapy). The rate of hyposomia (height < mean -2 SD) amounted in the whole group to 4.7 per cent. It rose in the extrinsic asthmatics to 6.6 per cent. This corresponds with a rise of two or three times the normal rate. 11.6 per cent of the probands showed a skeletal retardation of more than 2 years. The degree of BMD showed a significant dependence on age and type of asthma but not on the duration of the disease, severity or glucocorticoid therapy. Skeletal retardation cannot, therefore, be regarded as a direct consequence of bronchial asthma, whereas the significantly different averages of BMD in extrinsic and intrinsic asthmatics point to an atopic genesis, hence it might be possible to speak of an atopic retardation of the skeleton.(ABSTRACT TRUNCATED AT 250 WORDS)

The humoral activity of the avian thymic microenvironment.

The thymic microenvironment (composed of the lymphoepithelial stroma and the secretory products of the thymic epithelium) provides the required milieu for the development of the thymus-derived lymphocytes (T cells). There is limited information characterizing or identifying the active secretory components of the avian thymus. The work discussed here has focused on examination of the presence, regulation, and activity of one of the thymic hormones (thymulin) in the chicken. A thymulin-like product has been shown to exist in chicken serum as assessed by the mammalian bioassay and an ELISA immunoassay; thymectomy removes this product from the serum. Serum thymulin activity has been shown to be directly related to the thyroid status of the chick with the functionally hypothyroid Cornell sex-linked dwarf strain having lower levels than the euthyroid K strain. Alterations in circulating thymulin concentrations produced by daily thymulin injections resulted in an altered profile of the major peripheral blood T cell subpopulations and produced significant changes in the autoimmune pathology present within the Obese strain chicken. These approaches represent preliminary attempts to study the role of thymulin in avian immune development and in immune-neuroendocrine interactions.

Antibody deficiency and isolated growth hormone deficiency in a girl with Mulibrey nanism.

A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective antibody response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.

Cartilage-hair hypoplasia syndrome: immunological evaluation of two cases.

PURPOSE: Immunological evaluation of patients with cartilage-hair hypoplasia. TYPE: Prospective and retrospective studies. PLACE: Division of Allergy, Clinical Immunology and Rheumatology-Dept. of Pediatrics-"Escola Paulista de Medicina". PATIENTS: Two children with cartilage-hair hypoplasia syndrome. METHODS: Clinical and immunological evaluation. Humoral immunity (immunoglobulin levels, poliovirus antibodies, etc.) and T cell immunity (in vitro cultured lymphocytes stimulated with PHA, Con A and PWN, total T cell and subset determination) were studied. RESULTS: Cellular immunodeficiency and hypogammaglobulinemia were observed in one patient and normal values in the other. CONCLUSIONS: Immunological evaluation (cellular and humoral) should be performed in all patients with cartilage-hair hypoplasia.

Cartilage hair hypoplasia, metaphyseal chondrodysplasia type McKusick: description of seven patients and review of the literature.

We describe 7 cases of cartilage hair hypoplasia (CHH) with emphasis on the clinical and immunological aspects. The literature on CHH is reviewed and symptoms in 63 non-Amish cases are summarized. In this autosomal recessive disorder the immunodeficiency, hair abnormalities, and severity of skeletal involvement show extremely variable expressivity, between and within families. Two of the 3 sib-pairs among our cases demonstrate the great difference in expression within one family. At adult age roentgenological abnormalities can be very mild, or even absent. An impairment in cell-mediated immunity is present in all of our cases and seems a consistent manifestation in CHH; however, sometimes it is very subtle and without clinical symptoms.