Plasma TGF beta in systemic sclerosis: a cross-sectional study.

OBJECTIVES--To determine whether the active 25 kDa form of the fibrogenic cytokine transforming growth factor beta (TGF beta) can be detected in plasma from patients with systemic sclerosis and to examine the relationship between plasma TGF beta and clinical markers of disease severity and serum concentrations of the aminoterminal peptide of type III procollagen (PIIINP) (a laboratory marker of the fibrotic process). METHODS--A cross sectional study was made of 39 patients with systemic sclerosis (11 diffuse and 28 limited), nine patients with primary Raynaud's disease and 60 healthy controls. TGF beta 1 and TGF beta 2 were measured by enzyme linked immunosorbent assay (ELISA) (sensitivity 100 pg/ml) and PIIINP by radioimmunoassay. RESULTS--TGF beta 1 was detected in plasma from six of 39 patients with systemic sclerosis but not in any patient with primary Raynaud's disease or healthy controls. TGF beta 2 was not detected in plasma from patients or controls. No clear relationship was demonstrated between TGF beta 1, clinical features or PIIINP concentrations. CONCLUSIONS--The 25 kDa form of TGF beta 1 can be detected in the plasma of some patients with systemic sclerosis. This provides limited support for the hypothesis that this cytokine plays a role in the pathogenesis of this disease. However, longitudinal studies, particularly in early diffuse disease, are required to clarify the relationship between circulating TGF beta 1 and disease activity.     

Composition and function of peripheral blood stem and progenitor cell harvests from patients with severe active rheumatoid arthritis

High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 μg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 × 10⁶/kg, P = 0.03) and CD34⁺ cells (2.7 v 5.8 × 10⁶/kg, P = 0.003). However, there were increased proportions of CD14⁺ cells (P = 0.006) and CD14⁺CD15⁺ cells (the phenotype of previously described ‘abnormal’ myeloid cells, P = 0.002) in the RA PBSCH which translated into 3.5- and 7-fold increases respectively on a per CD34⁺ cell basis. There were no differences in T-cell activation status as judged by proportions of CD4⁺ and CD8⁺ expressing CD45RA, CD45RO, HLA-DR and CD28 (RA PBSCH, n = 7, donor PBSCH, n = 5, P = 0.2–0.7). Phytohaemagglutinin responses determined fluorocytometrically with induction of CD69 expression were reduced in CD4⁺ and CD8⁺ cells following filgrastim administration in 3/3 RA patients tested. Compared with bone marrow as a potential source of CD34⁺ cells, PBSCH contained 11-fold more T cells (P < 0.0005), 8-fold more B cells (P < 0.0005) and 4-fold more monocytes (P = 0.02). In short-term methylcellulose culture there were no differences in colony counts (CFU-GM, CFU-GEMM, BFU-E) per CD34⁺ cell from PBSCH from RA patients (n = 11) and healthy donors (n = 10). Long-term culture initiator cells were cultured successfully from cryopreserved PBSCH from RA patients (n = 9). In conclusion, PBSCH from RA patients differed significantly in composition from normal individuals, but in vitro studies support normal stem and progenitor cell function. Changes in T-cell function occur during mobilization in RA patients. This work provides reassurance for the use of PBSCH as haematological rescue and baseline data for clinical trials of graft manipulation strategies in patients with RA.     

Semantic-Episodic Memory Interactions in Semantic Dementia: Implications for Retrograde Memory Function

Semantic dementia refers to a multi-modal loss of semantic knowledge, resulting from degeneration of the anterior temporal neocortex. Loss of information is not absolute. We have previously demonstrated (Snowden, Griffiths,& Neary, 1994, 1995) that autobiographical experience has an important role in influencing information preservation, and have argued that patients' preserved experiential memory helps to invest words and objects with meaning that would otherwise be lost. Those studies suggested a particularly critical role of current autobiographical experience. The present study aimed to explore the generality of the observed current information superiority in an investigation of patients' knowledge of celebrities, understanding of a contemporary and obsolete monetary system, and autobiographical memory. Performance was superior for contemporary (recent) than for past (remote) information, both factual and autobiographic, suggesting an inverse of the temporally graded pattern of retrograde memory found in classical amnesia. It is argued that the findings are consistent with explanations of the "temporal gradient" effect of retrograde amnesia in terms of qualitative differences in recent and remote memories. The findings indicate a bidirectional interaction between autobiographic and semantic memorising, and emphasise a continuous, dynamic interrelationship rather than a time-limited role. An important distinction is highlighted between autobiographical and impersonal episodic memory. The findings have significant theoretical implications both for the understanding of retrograde memory function and the interrelationship between episodic and semantic memory.     

FcγRIIa polymorphism in systemic lupus erythematosus

OBJECTIVES—Polymorphism of the phagocyte IgG receptor FcγRIIa may modulate immune complex mediated inflammation, particularly when immune complexes contain IgG2. Previous studies suggest that this polymorphism may be an important risk factor for lupus nephritis. FcγRIIa is biallelic, the alleles R and H each having a gene frequency of about 50%. Nephritis has been associated with an increased frequency of the R allele. The frequency of common FcγRIIa alleles was examined in white subjects from the United Kingdom and Greek subjects with systemic lupus erythematosus (SLE) and healthy controls.
METHODS—FcγRIIa genotyping was performed using a single step polymerase chain reaction technique, which differentiates the two major alleles, R and H. Two study populations were examined: (a) white subjects from the United Kingdom : 66 controls and 81 with SLE (19 of whom had renal disease) and (b) Greek: 52 controls and 42 with SLE (19 with renal disease).
RESULTS—No significant relation was observed between FcγRIIa genotype and susceptibility to SLE or SLE nephritis.
CONCLUSIONS—The FcγRIIa R allele does not seem to be associated with SLE (with or without renal disease) in our United Kingdom white or Greek populations.

     

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.