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Biomedical subjects

R C Atkins

Publications and source records attributed to R C Atkins.

At least 145 records · Page 8Linked to original sources
PubMed1991

Deoxyspergualin inhibits cytotoxic T lymphocytes but not NK or LAK cells.

Deoxyspergualin (DOSP) is a new immunosuppressive agent which probably inhibits various functions of monocytes, B cells and T cells. We examined the effects of deoxyspergualin on cellular cytotoxicity, including cytotoxic T lymphocyte (CTL) mediated killer, natural killer (NK) cell and lymphokine activated killer (LAK) cell killing. Deoxyspergualin inhibited cellular cytotoxicity generated by 7 days allo-antigenic challenge; it also inhibited cell killing if added on day 6 of this 7 day culture period. The drug did not significantly inhibit NK or LAK cell killing. The inhibitory effects of deoxyspergualin, however, were dependent on the serum used in the culture medium. Normal human serum (NHS) was associated with less inhibition than fetal calf serum (FCS). Finally, interleukin 2 (IL-2) was able to prevent the inhibitory effects of deoxyspergualin on antigen-specific cytotoxicity.

CD8 Antigens↗
PubMed1991

Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis.

Most forms of glomerulonephritis have a significant interstitial leukocytic infiltrate which is associated with disease progression. However, there is little data concerning the timing, initial location, and development of this interstitial component. Therefore, we have addressed these issues in a study of passive accelerated anti-GBM glomerulonephritis in the rat. In this model, interstitial leukocytic infiltration was an early event in the disease process with a significant infiltrate apparent at 12 hours after administration of nephrotoxic serum (NTS). This initial infiltrate was restricted to a perivascular sheath surrounding the hilar arterioles. The sheath infiltrate then spread to include the whole hilar area by day 1, the entire periglomerular area by day 3, and became widespread throughout the cortical tubulointerstitium by day 7. The early sheath infiltrate was composed of macrophages and T cells. Both cell types continued to increase as the infiltrate expanded, and a significant accumulation of activated cells (IL-2R+) was evident from day 7 onwards. There was a highly significant correlation between interstitial macrophage infiltration and renal function impairment, proteinuria, and histologic damage. Interstitial T cell infiltration correlated with proteinuria and histologic damage, while the appearance of immune-activated mononuclear cells (IL-2R+) exhibited a highly significant correlation with all disease parameters. This study demonstrates the importance of the glomerular hilar arteriolar region as a focus for mononuclear leucocytic migration and accumulation which not only affects the structure and function of the glomerulus but subsequently the entire tubulointerstitium.

Animals↗
PubMed1991

Activated (IL-2R+) intraglomerular mononuclear cells in crescentic glomerulonephritis.

We recently reported evidence for the involvement of local cellular immune activation in the immunopathogenesis of human IgA nephropathy, particularly in cases of IgA disease featuring crescent formation. In the current study, using monoclonal antibodies, we investigated whether mononuclear cells bearing receptors for interleukin 2 (IL-2R+ MNC) were present within glomeruli or associated crescents in biopsies from patients with crescentic glomerulonephritis (greater than 60% crescents, N = 19), IgA disease with crescents (N = 9), or other types of proliferative glomerulonephritis with crescents (10 to 44%, N = 6), compared with normal control kidneys (N = 10). Biopsies were further classified into those showing active (cells, fibrin) (N = 15) or inactive (sclerosed) crescents (N = 19), to determine whether IL-2R+ MNC were particularly associated with active crescent formation. Few leucocytes were found within glomerular tufts of normal kidneys (2.4 +/- 0.7 cells/glomerular cross-section; mean +/- SEM). By contrast, in biopsies from patients with active crescentic glomerulonephritis, total intraglomerular tuft leucocytes were increased to 14.0 +/- 1.7 (P less than 0.01 vs. normal kidneys), largely due to increased numbers of intraglomerular monocytes (10.4 +/- 1.1, P less than 0.01) and T cells (3.7 +/- 0.6, P less than 0.01). Biopsies with active crescents also contained significantly increased numbers of intraglomerular tuft IL-2R+ MNC (4.0 +/- 0.7, 29% of total intraglomerular leucocytes), and there was a strong correlation between the numbers of intraglomerular IL-2R+ MNC and T cells (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Count↗
PubMed1991

Differential control of mesangial cell proliferation by interferon-gamma.

Rat mesangial cells were shown to be sensitive to recombinant interferon-gamma (IFN-gamma). IFN-gamma reduced thymidine uptake by these cells and inhibited cell proliferation. Incubation of the cells with 1000 U/ml IFN-gamma decreased thymidine uptake by up to 64% and cell numbers were decreased by 17%. The effects of IFN-gamma were dose and time dependent and were partially reversible by the anti-IFN-gamma monoclonal antibody DB-1. This lymphokine did not reduce incorporation of RNA and protein precursors however. Measurements of 3H-uridine and 3H-leucine incorporation indicated significant increases in RNA and protein synthesis (37% and 45%, respectively) on a per cell basis. The mitogenic effects of IL-1 and platelet-derived growth factor (PDGF) were also susceptible to IFN-gamma-mediated inhibition but the mitogenic response to epidermal growth factor (EGF) was much less sensitive. We conclude that while IFN-gamma may act to modulate the mitogenic signals provided by some factors such as IL-1 and PDGF, the response to EGF appears to be unaffected.

Animals↗
PubMed1991

Anthropometry underestimates body protein depletion in haemodialysis patients.

The body composition of 62 haemodialysis patients (41 males) and 63 controls (30 males) was assessed using anthropometry and in vivo neutron activation analysis of body nitrogen. There was no significant difference between patients and controls in body mass index (BMI) and percentage body fat. Arm muscle circumference was significantly reduced in males. Lean body mass was strongly correlated with body nitrogen in controls (r = 0.951) but less so in patients (r = 0.876). The mean standardised body nitrogen index (NI) was reduced in male patients by 13% (95% confidence interval -9 to -17%) and in females by 4% (95% confidence interval +4 to -12%). Of the 16 patients with a NI below the control range, arm muscle circumference was below the control range in only 3 and BMI less than 18 kg/m2 in 2. NI was correlated negatively with the duration of renal replacement therapy, duration of haemodialysis, the number of previous failed transplants and the total dose of steroids received but not with current energy or protein intakes. Steroid dose was the only significant independent variable. Anthropometry underestimates body protein depletion in haemodialysis patients and the degree of protein loss is related to the cumulative dose of corticosteroids previously received.

Adrenal Cortex Hormones↗
PubMed1991

The evolution of the interstitial infiltrate in rejecting rat renal allografts: with particular reference to the production of gamma-interferon.

This study aimed to examine the evolution of the leucocytic infiltrate in rat renal allografts in the first 5 days of rejection. Immunohistology was used to assess the absolute numbers of infiltrating leucocytes in the rejecting allografts. The total infiltrate approximately doubled daily from day 1 through to day 4 (370 +/- 15 total leucocytes/mm2 of tissue on day 1 vs 5055 +/- 135 on day 4, p less than 0.05 for all days) and increased only a minor degree on day 5 (5485 +/- 535 leucocytes/mm2, p = n.s.). CD4 positive cells predominated until day 3, after which time CD8 positive cells greatly outnumbered CD4 positive cells (CD4:CD8 ratio day 3 1.83 vs day 5 0.53, p less than 0.05). Gamma-interferon was positive in T cells on day 2 (73% of all T cells) and was slightly positive on day 3 (5% of all T cells) but was negative on days 4 and 5. Activation markers such as IL-2Rs increased markedly from day 3. These findings favour a pivotal role for CD4 positive cells in the early phase of rejection and suggest that the early release of lymphokines by these cells is associated with the recruitment of CD8 positive cells to the allograft and the activation of those leucocytes present.

Animals↗
PubMed1991

Leukocyte involvement in the pathogenesis of pulmonary injury in experimental Goodpasture's syndrome.

To investigate the role of leukocytes in the pathogenesis of pulmonary injury after antibody deposition on the alveolar basement membrane, we have induced experimental Goodpasture's syndrome in the rat using passive accelerated anti-glomerular basement membrane (GBM) disease. Animals were immunized with normal rabbit IgG and given either rabbit anti-rat GBM serum or normal rabbit serum (control) 5 days later. In this model, leukocytic infiltration, severe hemorrhage, and granulomatous-like lesions developed in the lung, while a rapidly progressive glomerulonephritis was evident in the kidney. Within 30 minutes of injection of anti-GBM serum, strong linear deposition of antibody on both glomerular and alveolar basement membranes was evident. In the lung, a transient influx of polymorphonuclear cells during the first 12 hours was closely followed by macrophage infiltration, with T cell infiltration not evident until day 3. Pulmonary hemorrhage correlated with ED1+ macrophage infiltration (p less than 0.001), but not with OX-19+ T cell accumulation. Many activated mononuclear cells were found in the lung infiltrate from day 14 onward and were associated with areas of tissue damage. This study demonstrates the feasibility of using passive accelerated anti-GBM disease as a model of Goodpasture's syndrome, and suggests that inflammatory macrophages are the major cellular participants in progressive pulmonary injury after antibody deposition.

Animals↗
PubMed1990

T cells and CD45R expression in B-chronic lymphocytic leukemia.

A major secondary immunodeficiency exists in B cell derived chronic lymphocytic leukemia (B-CLL) which involves both humoral and cellular immunity and is largely unexplained. Several T cell subset redistributions have been noted in B-CLL. We therefore examined in more detail the immunophenotype of T cells by assessing CD45R expression using a two-colour immunofluorescence technique. The proportion of CD45R+ cells among CD3+, CD4+ and CD8+ cells in B-CLL was significantly (p less than 0.001) higher than in corresponding normal cell populations. We also sought relationships between major T cell subsets and progress of disease and found strongly positive correlations between the total leukocyte count in B-CLL and numbers of CD3+, CD4+, CD8+ cells and monocytes. Further, in patients with clinically more advanced disease, CD3+ and CD4+ cells were present in higher numbers than in patients with less advanced disease (p less than 0.05). CD8+ cells, CD4/CD8 ratio, monocytes and total leukocyte count were not significantly different when comparing the less advanced and more advanced disease patients. An excess of CD45R+ suppressor-inducer T cells has implications for both B and T cell dysfunction and for disease progression.

Antibodies, Monoclonal↗
PubMed1990

Mononuclear cell activation and decreased renal function in IgA nephropathy with crescents.

Our previous immunohistologic studies with monoclonal antibodies (mAb) showed that glomerular and interstitial accumulations of mononuclear cells (MNC) were common features of many types of proliferative glomerulonephritis, especially crescentic glomerulonephritis. The current study examined a series of patients with crescentic IgA disease, since IgA disease in general has a highly variable course and the presence of crescents is one indicator of likely progression to end-stage renal failure. We compared the intraglomerular and interstitial infiltrates within biopsies from patients with crescentic IgA nephropathy (N = 5) versus those with noncrescentic IgA (N = 18), or normal controls (N = 10). Few leucocytes were found within glomeruli of normal (2.4 +/- 0.7 cells/glomerular cross section) (mean +/- SEM) or noncrescentic IgA disease biopsies (3.8 +/- 0.7), and no activated MNC bearing receptors for interleukin-2 (IL-2R) were detected. By contrast, in crescentic IgA disease, glomerular leucocytes were increased (5.1 +/- 0.6, P less than 0.01), due to increased monocyte (3.1 +/- 0.9, P less than 0.01) and T cell (1.4 +/- 0.4, P less than 0.01) infiltration, and IL-2R + MNC were then observed (1.2 +/- 0.5, P less than 0.05). Studies of interstitial cells showed small numbers of leucocytes within normal kidneys (101 +/- 16/mm2). Biopsies from noncrescentic IgA disease showed a fivefold increase in interstitial MNC infiltration (total leucocytes 565 +/- 105/mm2, P less than 0.01), due to an influx of T cells (283 +/- 59/mm2, P less than 0.01) and monocytes (120 +/- 32/mm2, P less than 0.01), and including a mean of 20% IL-2R+ MNC (114 +/- 29/mm2, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Contribution of mononuclear leucocytes to the progression of experimental focal glomerular sclerosis.

Uninephrectomized Sprague-Dawley rats repeatedly administered with aminonucleoside of puromycin and protamine sulfate developed progressive focal glomerular sclerosis (FGS). The contribution to disease progression of both glomerular and interstitial infiltrating leucocytes was studied throughout the disease evolution. Leucocyte subsets were quantitated with an immunoperoxidase technique using monoclonal antibodies for rat leucocyte surface antigens: OXI (total leucocytes) OX6 (Ia positive cells), OX8 (suppressor/cytotoxic T cells), OX19 (total T cells), OX22 (B cells and subsets of T cells), and ED1 (macrophages/monocytes). In the glomeruli, macrophages and Ia positive cells were significantly increased when sclerotic lesions appeared, but T lymphocytes and subsets of T lymphocytes were not found. However, in the interstitium, all leucocytes were identified and increased in number throughout the disease evolution. Early in the disease, monocytes and lymphocytes were both present in large numbers, but at the end stage of the process, the predominant infiltrating leucocytes were CD4+ve T cells. In FGS rats treated throughout the disease with oral prednisolone (begun after disease induction), renal function was significantly better than in the untreated group, whereas the sclerosis and leucocyte accumulation in the glomeruli were unchanged. However, prednisolone treatment resulted in significantly fewer interstitial leucocytes and especially reduced the numbers of CD4+vc cells. These results suggest that the glomerular sclerotic lesions are related to the participation of macrophages independent of T cells, and that immune mechanisms mediated by T cells in the interstitium have an important role in the progression of this disease to end-stage renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Defective cytostatic activity of pulmonary alveolar macrophages in primary lung cancer.

Macrophages are thought to play an important immune effector cell role in antitumor host defense. It remains unclear whether PAM antitumor activity in patients with lung cancer is normal or impaired. We examined PAM cytostasis in patients with lung cancer and in control subjects and determined whether the in vitro PAM response could be enhanced by gamma-interferon. Nineteen patients with primary lung carcinoma and 15 control patients underwent BAL. Five patients with cancer underwent lavage of both lungs to assess whether any abnormality found related to tumor proximity or was part of a more generalized defect. Cytostatic activity was assessed by measuring inhibition of incorporation of tritiated thymidine into the target cell U937. There was a significant difference in baseline cytostatic activity between patients with cancer (mean +/- SE, 59 +/- 7 percent) and control patients (92 +/- 2 percent) (p less than 0.0002). The increase in cytostatic function after stimulation with gamma-interferon (1,250 units/ml) was higher in the group with cancer (28 +/- 5 percent increase from baseline) than in controls (5 +/- 1 percent) (p less than 0.0005). Cytostasis after stimulation was not significantly different between the groups. In the bilaterally lavaged group, baseline cytostatic activity was not different between cancerous and noncancerous lungs and was again significantly lower than in control subjects. These results indicate (a) that PAM baseline cytostatic activity in patients with cancer is lower than in controls, (b) that gamma-interferon can significantly augment cytostatic function in patients with cancer, to levels comparable with those achievable in control patients, and (c) that the PAM abnormality is part of a generalized immune defect in lung cancer and does not simply reflect a local response to the carcinoma. It may be inferred from these results that PAMs from patients with primary lung cancer are not fully stimulated in vivo and that a defect of T cell lymphokine production may underlie the macrophage dysfunction.

Adult↗
PubMed1989

Retinoic acid affects the cell cycle and increases total protein content in epithelial cells.

Retinoids and particularly retinoic acid (RA) have been incriminated in the adaptation to uninephrectomy and compensatory kidney growth in humans. However, there is no data assessing the effects of RA on renal cells. Since the bulk of the compensatory kidney growth is due to tubular cells, we studied the effects of RA, retinol and epidermal growth factor (EGF) on a rabbit kidney epithelial cell line RK13 in culture. RA significantly increased thymidine incorporation by 42 +/- 8% (P less than 0.01). This increase appeared as soon as three hours after adding RA and could still be observed after five days. Total protein content was also increased by RA by 37 +/- 4% (P less than 0.01). Flow cytometer analysis showed a significant decrease in the percentage of resting cells (G0-G1 phases) induced by RA (-9.4 +/- 2%; P less than 0.01). We observed similar results in growth factor free medium, and the RA induced changes were the same in confluent and non-confluent cells. Retinol did not modify thymidine incorporation or total protein content. EGF increased by 75% thymidine incorporation (P less than 0.01). In serum free conditions RA failed to have a synergistic effect with EGF. These data show that RA is able to induce modifications in kidney epithelial cells compatible with those observed in hypertrophy while retinol is not. These modifications are not due to other growth factor potentiation but to RA itself, and are independent of the contact-inhibition phenomenon.

Animals↗