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Biomedical subjects

R C Atkins

Publications and source records attributed to R C Atkins.

At least 163 records · Page 9Linked to original sources
PubMed1989

The effects of OKT3 therapy on infiltrating lymphocytes in rejecting renal allografts.

OKT3 antibody therapy is effective in the treatment of renal allograft rejection. However its exact mode of action is unknown. Following OKT3 administration, peripheral blood lymphocytes fail to express the CD3 antigen, although other membrane antigens are relatively preserved. In this way the lymphocytes are unable to respond to foreign antigens. It is not known whether this modulation of CD3 on lymphocytes occurs within the rejecting allograft. Ten patients who received OKT3 therapy for steroid-resistant renal allograft rejection were studied. The aim of the study was to examine whether OKT3 antibody therapy altered the degree or the relative composition of the inflammatory infiltrate and to assess whether OKT3 treatment resulted in modulation of CD3 on intragraft lymphocytes. The study involved immunoperoxidase examination of biopsy material and flow cytometric analysis of peripheral blood lymphocytes obtained before and during treatment with OKT3 antibody. The results show that the total number of infiltrating leukocytes decreased after 5 days of treatment (3215 +/- 700 cells/l. 0 mm2 of tissue before vs. 1730 +/- 635 at day 5; P less than 0.001). The relative proportions of macrophages, total lymphocytes, CD4 +ve and CD8 +ve cells did not alter during therapy. Despite marked modulation of peripheral blood lymphocytes (CD3/CD2 ratio 0.89 +/- 0.13 before vs. 0.10 +/- 0.11 during treatment, P less than 0.001), there was no evidence of modulation of intragraft lymphocytes (CD3/CD2 ratio 0.98 +/- 0.14 before vs. 0.90 +/- 0.21 during treatment, P = NS). Although OKT3 antibody therapy is effective clinically at improving renal allograft rejection, this study demonstrates that it does not appear to cause modulation of the CD3 antigen on intragraft lymphocytes.

Adult↗
PubMed1989

Phenotypic definition of primed T cells in human renal allografts. Use of the CD45R marker.

Immunohistological studies indicate that T cells and macrophages are the major components of human kidney allograft infiltrates. Recent work has demonstrated a division of T lymphocytes into 2 subpopulations with distinct functions on the basis of their expression of the CD45R antigen (CD45R+ "naive" and CD45R- "memory" T cells). This study analyzes CD45R expression on circulating T cells and T cells infiltrating renal allografts in patients undergoing rejection and/or cyclosporine nephrotoxicity. The percentage of circulating T cells that expressed CD45R in patients with rejecting (63 +/- 4) or stable grafts (66 +/- 3) was not different from values obtained for normal donors (62 +/- 3). In contrast, the percentage of T cells expressing CD45R infiltrating rejecting grafts was 21 +/- 2 and was not affected by the stage of rejection; in patients with CsA toxicity the value was 22 +/- 6. The reduced proportion of T cells that expressed CD45R in the allograft may reflect a change in status from the naive state due to alloantigenic stimulation (which can be demonstrated in vitro) and/or a propensity of memory T cells to enter or be retained in an allograft.

Antigens, CD↗
PubMed1989

The effects of deoxyspergualin on lymphocytes and monocytes in vivo and in vitro.

It has been suggested that deoxyspergualin, a new immunosuppressant, may be immunosuppressive via a purely antimonocyte action. As this appears to be unlikely, this study examines the effect of deoxyspergualin on lymphocyte and monocyte function in vivo and in vitro. It is demonstrated that deoxyspergualin inhibits human lymphocyte proliferation in response to mitogens and allogeneic stimulation. Furthermore, it is demonstrated that this inhibition occurs no matter whether the monocytes or lymphocytes are treated with the drug. The drug appears to have a more significant effect on the lymphocyte component; rhIL-2 appears partly to overcome the deoxyspergualin-induced inhibition of lymphocyte proliferation in response to allogeneic stimulation. In a rat renal transplant model, deoxyspergualin-treated animals demonstrated a moderate interstitial infiltrate in their transplant kidneys that comprised approximately 50% each of macrophages and lymphocytes. There was significantly less activation (e.g. IL-2R expression) in the treated kidney infiltrates compared to rejected controls. Thus deoxyspergualin is an agent with immunosuppressive effects on both lymphocytes and monocytes and would appear to have more marked effects on lymphocytes.

Cyclosporins↗
PubMed1989

Ultrastructural immunoperoxidase investigations of human glomerular cells in tissue culture.

In order to elucidate the cells produced from human glomerular cultures, a pre-embedding ultrastructural immunoperoxidase technique was developed to investigate the precise localisation of a panel of monoclonal antibodies specific to human glomerular antigens in situ and used to identify the same antigens in vitro. The results obtained were correlated with the morphological features of the cells demonstrated by scanning electron microscopy. The study was able to show the presence of epithelial and mesangial cells in tissue culture, to confirm previous results indicating that glomerular endothelial cells are not present and to give some insight into the production of different basement membrane components by different cell types.

Antibodies, Monoclonal↗
PubMed1989

Glomerular cells and macrophages in the progression of experimental focal and segmental glomerulosclerosis.

To determine the characteristics of glomerular cell involvement in experimental focal and segmental glomerulosclerosis (FGS) in rats induced by repeated injections of aminonucleoside of puromycin (PAN) and protamine sulfate (PS), glomeruli were isolated and grown in tissue culture. When compared with saline controls the FGS rats had decreased rates of glomerular attachment and significantly reduced outgrowths of type 1 (epithelial) and type II (mesangial) cells. However, the FGS rats had greater numbers of type III cells (macrophages) present in the outgrowths than controls. The production of interleukin-1 (IL-1) in the glomerular culture supernatant, measured by thymocyte stimulating activity, was determined at various stages throughout the evolution of FGS and in saline controls. The FGS glomeruli early in the disease course (day 10) had higher levels of IL-1 activity than glomerular outgrowths from control rats but significantly lower levels of IL-1 were produced late in the disease (day 80). Glomerular macrophages were present throughout the evolution of the disease but in greater numbers early (day 10). In this experimental model of FGS, IL-1 production, has been demonstrated early in the disease process, could originate from macrophages and/or mesangial cells, and could be involved in the progressive glomerulosclerosis.

Animals↗
PubMed1988

Human macrophage maturation and heterogeneity: restricted expression of late differentiation antigens in situ.

Terminal maturation of human macrophages is an important step for creation of cell diversity amongst site-specific subpopulations and their functional competence in situ. As monocytes undergo differentiation in vitro, they start to express lineage-restricted antigens specific for differentiation stages beyond the blood monocyte level as detected by monoclonal antibodies of the MAX series. We have analyzed the expression of MAX.1, MAX.2, MAX.3 and MAX.11 on exudate-type macrophages from pleural and peritoneal cavity and the alveolar space, as well as on resident and activated tissue macrophages in cryostat sections of spleen, lymph node, tonsil, liver, gut mucosa, skin, placenta, kidney and bone. It was found that "free" macrophages in serous cavities expressed MAX antigens in a heterogenous pattern, whereas none of the organ-specific tissue macrophages subsets did so (with the exception being the weak label of MAX.2 on Kupffer cells). Only during allograft rejection were infiltrating macrophages found to express MAX antigens but not at sites of "non-specific" inflammation or granuloma formation. However, Cyclosporin A treatment seems to suppress the induction of MAX antigen expression on intragraft macrophages. In addition, freshly harvested MAX-negative exudate macrophages converted to the complete Max+ phenotype on further cultivation. Isolated Kupffer cells were able only to express the MAX.2 antigen in culture but still did not react with the MAX.1 and MAX.3 monoclonal antibodies. Some MAX antigens are co-expressed on glomerular mesangial cells, dendritic reticulum cells and placental cells (MAX.1/.11) as well as on capillary endothelium within tissues of active immune response (MAX.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1988

Human macrophage maturation in vitro: expression of functional transferrin binding sites of high affinity.

Human blood monocytes (mo) when cultured in suspension on hydrophobic teflon membranes undergo terminal maturation to macrophages (MO). Together with the appearance of new lineage-restricted differentiation antigens, mature MO but not blood mo, express transferrin (TF) receptor molecules as detected by immunostaining methods. Here we report that radio- and fluorescein-labelled TF binds to a single class of high-affinity binding sites on MO but not on mo. As mo mature in vitro in the presence of human serum, their receptor numbers increase to about 10(6) per cell, showing an apparent Kd for Fe2TF of approximately 5 nM. These receptor numbers were comparable with our estimates for cultured K 562 human tumor cells, and about 20x greater than reported for human MO cultured in the presence of fetal calf serum. Our MO showed 58Fe uptake comparable with uptake by tumor cells and also exhibited TF-promoted uptakes of 61Ga. The possibility that MO might recycle stored iron through receptor-bound apoTF was not supported by experiments which showed that their Fe2TF receptors had much lower affinity for apoTF (Kd greater than 1 microM) and which could not detect separate high-affinity receptors specific for apoTF. Expression of TF receptors was not substantially altered by treatment with human recombinant interferon-gamma.

Cell Division↗
PubMed1988

Activation of human monocyte-derived macrophages cultured on Teflon: response to interferon-gamma during terminal maturation in vitro.

Macrophages (M phi) are potential antitumor effector cells derived from circulating blood monocytes (mo). Most studies on human mo/M phi biology and function have been performed using immature mo precursor cells. However, the conclusions drawn may be questionable, as mo have to undergo terminal differentiation before they reach relevant tissue sites of inflammation and immune reaction. We have analyzed the ability of mo-derived, teflon-cultured M phi to respond to activating stimuli with an increased tumor cytotoxic effector cell function using recombinant interferon-gamma (IFN-gamma), IFN-alpha 2, granulocyte/macrophage colony stimulating factor (GM-CSF), interleukin(IL) 2, IL 1 alpha, and bacterial lipopolysaccharides (LPS) as mediator molecules. It could be shown that the response of M phi to the most potent activator molecule, IFN-gamma, depends on the terminal differentiation from the mo stage to the mature M phi. Whereas adherent mo could be activated only moderately, M phi increased their cytotoxicity by a factor of up to 400. IFN-gamma activation positively correlated with the effector cell number, the time of incubation and the dosage used. Activation did not depend on the presence of LPS, and was lost within 24 to 48 h. LPS itself activated cells only in the microgram range. IFN-alpha 2 activated M phi only at a two log higher concentration than IFN-gamma; GM-CSF was only slightly effective, whereas M phi incubation with IL 1 alpha or IL 2 did not result in M phi activation. Thus, the ability of human M phi to become activated appears to be a function of cellular maturation and is acquired during the terminal step of M phi differentiation. Teflon-cultured M phi could facilitate studies of the activation of human M phi and may be more suitable cells for adoptive immunotherapy in cancer patients than blood monocytes.

Cell Differentiation↗
PubMed1988

Nonhepatitis B-associated liver disease in a renal transplant population.

The spectrum of liver disease in a population of 293 patients receiving 353 renal transplants (1971-1984) was reviewed. This study looked retrospectively at the histological features of liver disease in this population, and prospectively at the clinical and biochemical features of liver disease associated with renal transplantation. In all patients, infection with hepatitis B was excluded. Six deaths, primarily attributable to hepatic failure have occurred: one, acute herpes simplex infection; one, subacute massive hepatic necrosis of uncertain etiology; two, pretransplant liver disease; and two, posttransplantation cirrhosis of uncertain etiology. Review of the hepatic histology of 26 patients with known liver disease following transplantation revealed a wide range of pathologies with few specific correlations with their clinical status or biochemical tests of liver function. The prevalence of hepatic dysfunction following transplantation in our patient population was assessed by prospective biochemical screening of 111 transplant recipients over a 6-month interval. During this time period, 27 patients (24%) displayed biochemical evidence of hepatic dysfunction. Liver disease was known to have predated transplantation in only three of 27. Episodes of abnormal liver function occasionally occurred during an identifiable acute illness (six of 27), although the majority (21 of 27) had chronic hepatic dysfunction. Transplant recipients with abnormal liver function could not be differentiated from a cohort with normal liver function on the basis of age, sex, duration of graft function, or alcohol/drug intake. The possible etiologies of nonhepatitis B liver dysfunction following renal transplantation are discussed, and the high prevalence of biochemical evidence of hepatic dysfunction in this population free of hepatitis B infection is emphasized.

Adult↗
PubMed1988

Intraperitoneal (IP) vancomycin therapy for CAPD peritonitis--a prospective, randomized comparison of intermittent v continuous therapy.

The use of intraperitoneal (IP) vancomycin as initial, single agent therapy for gram positive and "no organism" continuous ambulatory peritoneal dialysis (CAPD) peritonitis is described, comparing continuous and intermittent administration schedules. "Continuous" therapy consisted of an IP 1-g loading dose of vancomycin followed by 30 mg/L dialysate effluent. "Intermittent" therapy consisted of 2 IP doses of 30 mg vancomycin/kg body weight--the initial dose delivered at diagnosis and the second dose 1 week later. All patients presenting with peritonitis (n = 90) were randomized to receive either continuous or intermittent vancomycin therapy. Patients in whom gram negative organisms and fungi were identified by microscopy and culture were transferred to therapy with a more appropriate antibiotic (n = 39). In the remainder (n = 51), CAPD peritonitis was treated solely with vancomycin (continuous, n = 21; intermittent, n = 30). Clinical resolution was seen in all patients, requiring a mean of 3.2 days for macroscopic clearing of dialysate effluent. Recurrence of peritonitis within 1 month of cessation of therapy was unusual and did not vary between treatment protocols (4/21 v 3/30; P = NS). There were no differences in observed side effects. Thus, IP vancomycin proved to be a useful single agent therapy for gram positive and no organism CAPD peritonitis. Therapy with two IP doses was effective and as safe as continuous IP vancomycin therapy, and therefore should replace other vancomycin administration schedules in the treatment of CAPD peritonitis.

Drug Administration Schedule↗
PubMed1988

Cytomegalovirus infection complicating renal transplantation and its relationship to acute transplant glomerulopathy.

The incidence of cytomegalovirus (CMV) infection was established, using laboratory criteria, in 298 patients receiving 362 renal allografts (164/298 = 55%). The incidence of CMV infection did not differ between azathioprine/prednisolone-treated and cyclosporine-treated patients (55% vs. 57% NS). The use of antithymocyte globulin (ATG) increased the incidence of CMV infection (78% vs. 51%: P less than 0.01). Donor and recipient CMV status, known for 116 allografts, did not correlate with the incidence of CMV infection (recipient CMV-positive = 50%; recipient CMV-negative = 54%: NS). CMV infection was responsible for 8 patients' deaths (2.7% mortality). Thirty-three patients with acute transplant glomerulopathy were identified (11%). There was no correlation between acute transplant glomerulopathy and CMV infection. Glomerulopathy was associated with poor graft survival (22/33 patients with a graft survival of less than 6 months). Thus CMV infection, although a common complication of renal transplantation with significant morbidity and mortality, is not closely associated with acute transplant glomerulopathy. Further, the lack of correlation of donor-recipient CMV serologic status with graft outcome limits the usefulness of pretransplantation donor screening.

Acute Disease↗
PubMed1988

Production of interleukin 1 in glomerular cell cultures from patients with rapidly progressive crescentic glomerulonephritis.

Interleukin 1 (IL-1) activity was measured in glomerular culture supernatants from 3 patients with rapidly progressive crescentic glomerulonephritis (RPGN). Macrophages were present in both capillary tufts and cellular crescents as identified by OKM1-positive cells on immunoperoxidase labelling. Glomeruli from 4 rejecting renal cadaver allografts were used as a disease control, in addition to glomeruli from a normal kidney. IL-1 activity as measured by the thymocyte proliferation assay was greater in the supernatants from cultured glomerular outgrowths of patients with crescentic GN than in those from rejected renal allografts and glomeruli isolated from the normal tissue. IL-1 production from cultured glomerular cells from patients with RPGN was detectable in the serum-free conditioned media harvested after 3 days of culture and increased in a stepwise fashion over 28 days of culture. The prominent feature of the glomerular outgrowth of the glomeruli in the RPGN patients was the presence of large numbers of macrophages, which were not present in cultured control glomeruli. These findings indicate that the immunoregulatory aberration in patients with RPGN may in part be due to IL-1 production by activated macrophages.

Acute Disease↗