Biomedical subjects

A Tarkowski

Publications and source records attributed to A Tarkowski.

At least 163 records · Page 9Linked to original sources

PubMed1992

Anti-inflammatory properties of estrogen. I. In vivo suppression of leukocyte production in bone marrow and redistribution of peripheral blood neutrophils.

We have recently demonstrated that estrogen has differential immunomodulatory properties in mice because it stimulates antibody responses but inhibits T cell-mediated inflammation. In the present study we have examined the influence of estrogen on T cell-independent inflammatory responses. A local inflammation was induced by intradermal injection of olive oil and cholera toxin. Treatment of castrated mice with pharmacological and even physiological doses of estradiol significantly suppressed the inflammatory response, as measured by footpad swelling and documented by histologic examination. Even a single injection of a low dose of estradiol (3.2 micrograms/mouse) given up to 4 days prior to the administration of the phlogistic compound reduced the inflammatory response. Our results demonstrate that the mechanisms whereby estrogen exerts its anti-inflammatory property are probably not mediated by modulation of corticosteroid production. Instead, it is evidenced that estrogen significantly suppresses the bone marrow production of leukocytes and affects the distribution of polymorphonuclear cells in peripheral blood. The possible implications of our results are discussed in the context of the modulation of inflammatory rheumatic diseases.

Animals↗

PubMed1992

Histopathological and serological progression of experimental Staphylococcus aureus arthritis.

In a newly developed mouse model of Staphylococcus aureus arthritis the kinetics of joint destruction and serological manifestations as well as the clinical course of arthritis and osteitis were studied. Almost all mice developed histopathological signs of arthritis upon a single intravenous injection of 10(7) S. aureus LS-1 cells. There was rapid joint destruction, with synovial hypertrophy already visible, within 24 h after injection of the bacteria. Cartilage and/or bone erosions were seen in a majority of the mice within 72 h. Extra-articular manifestations, especially signs of bone infection, were also found soon after inoculation of the bacteria. Tail osteitis was frequent (50% of the mice) but appeared later than arthritis. Polymorphonuclear cells prevailed in the early joint lesions and were also common in the extra-articular manifestations. Within 3 days, mononuclear cells were also seen in the inflamed synovium, gaining a dominant position 3 weeks after the start of the disease. Serum interleukin-6 levels were already increased within 6 h after bacterial injection and remained elevated throughout the course of arthritis. Serum tumor necrosis factor levels were increased within 24 h. There was a tremendous induction of immunoglobulin production, especially of the immunoglobulin G1 isotype. This was paralleled by the production of specific antibodies to S. aureus (cell walls and toxin), as well as autoantibodies (rheumatoid factors and anti-single-stranded DNA antibodies), all predominantly of the immunoglobulin G isotype. The type and magnitude of the immunoglobulin G response together with the elevated interleukin-6 levels speak in favor of both antigen-specific and polyclonal B-cell activation during S. aureus arthritis. This study points out important similarities between our new model of S. aureus arthritis and human S. aureus arthritis. This resemblance will enable controlled studies of pathogenetic mechanisms of septic arthritis as well as therapeutic and prophylactic approaches.

Animals↗

PubMed1991

M-component with reactivity against actin associated with thrombotic thrombocytopenic purpura.

A patient with a monoclonal B-cell disorder producing an M-component with antiactin activity is described. After more than 3 years of observations, the final diagnosis is not completely established, but a malignant lymphoproliferative process is evidently under evolution. On three occasions, she has presented with symptoms compatible with a thrombotic thrombocytopenic purpura-like syndrome, concomitant with an increase in paraprotein. A relationship between this autoantibody and the patient's symptoms is proposed. Steroids have so far had a beneficial effect on the symptoms.

Actins↗

PubMed1991

Enhancement of antigen-specific T-cell reactivity on the affected side in stroke patients.

We have analyzed the impact of stroke with subsequent hemiparesis and sensory loss on in vivo mediated immune functions. The delayed-type hypersensitivity (DTH) reaction to purified protein derivate (PPD, tuberculin) was used as a measure of antigen-specific T-cell reactivity, and subcutaneous immunization with influenza vaccine was employed to evaluate T-cell-dependent B-cell function. Thirty-two of the 50 stroke patients tested displayed positive DTH reaction to PPD. All but two showed equal or stronger DTH reaction on the paretic arm compared to the contralateral side (p less than 0.0001). This stroke-induced enhancement of DTH reactivity was evident in patients with combined motor and sensory deficit as well as in subjects with hemiparesis alone. In contrast, immunization of stroke patients with influenza vaccine, a T-cell-dependent B-cell antigen, raised equal antigen-specific serum IgG, IgA and IgM antibody responses irrespective of side (paretic or not paretic). We conclude that stroke enhances antigen-specific T-cell reactivity on the affected side of the body, and that motor but not sensory deficit seems to be required for this enhancement. Antigen-specific B-cell reactivity was not significantly influenced by the hemiparesis.

Aged↗

PubMed1991

Differential effects of oestrogen in murine lupus: acceleration of glomerulonephritis and amelioration of T cell-mediated lesions.

Oestrogen is known to accelerate glomerulonephritis and autoantibody production in human and murine systemic lupus erythematosus (SLE). In this study we demonstrate that treatment of castrated autoimmune MRL +/+ mice with physiological doses of oestrogen results in enhanced immunoglobulin and autoantibody production as well as increased deposition of IgG in renal glomeruli. Accelerated development of glomerulonephritis was also evident from the increase of albuminuria. Interestingly, in contrast to these deteriorative effects of oestrogen on immune complex-mediated disease we now show that the lymphocytic infiltrations in the submandibular glands and perivascular lesions in the kidneys were significantly diminished after exposure to oestrogen. This remarkable impact of physiological oestrogen levels on the outcome of SLE in MRL +/+ mice is postulated to be the result of a differential effect on T and B cell-mediated immune responses.

Animals↗

PubMed1991

Cellular origins of human polymeric and monomeric IgA: enumeration of single cells secreting polymeric IgA1 and IgA2 in peripheral blood, bone marrow, spleen, gingiva and synovial tissue.

Using modified ELISA and spot-ELISA, which permit the parallel determination of heavy chain subclass and the presence of covalently linked J chain, we analysed IgA found in cell culture supernatants or secreted by individual cells from peripheral blood, spleen, bone marrow, gingiva and synovial tissue, with respect to its polymeric or monomeric IgA form (pIgA, mIgA) and IgA1 or IgA2 subclass. The ELISA for determination of J chain in tissue culture supernatants was specific and highly sensitive (detection limit in pg). The results demonstrated that IgA1-producing cells predominated in the tissues examined, and that J chain could be detected in association with the majority of IgA1 and IgA2 secreted by individual cells. With respect to the frequency of cells secreting polymeric, J chain-containing IgA, only 20-30% of cells from the bone marrow were engaged in the synthesis of PIgA. In other tissues the frequency of cells secreting pIgA1 and pIgA2 was considerably higher. Peripheral blood mononuclear cells secreting pIgA2 were easily inducible during stimulation with T cell-dependent pokeweed mitogen, whereas Epstein-Barr virus-transformed cells secreted preferentially mIgA1. When the frequencies of pIgA-, pIgA1- or pIgA2-secreting cells (determined by spot-ELISA technique) from different tissues were correlated with the proportion of pIgA to mIgA (and IgA subclasses) secreted in tissue culture supernatants, data obtained suggest that many individual IgA-producing cells could be engaged in simultaneous secretion of mIgA and pIgA.

Adult↗

PubMed1991

Reversal of T-cell anergy in autoimmune (NZB x NZW)F1 mice by transfer with non-antigen specific CD4+ T cells from young, syngeneic donors.

The F1 hybrid of NZB and NZW mice is a well-known model of systemic lupus erythematosus characterized by B-cell hyperactivity, production of autoantibodies and immune-complex formation. These phenomena have been regarded as pathogenetic for the development of glomerulonephritis and early death in renal failure. It has been previously reported that aged and overt diseased NZB/W mice also display impaired T-cell responses. In the present report we demonstrate an age-dependent decline in the capacity of NZB/W mice to mount in vivo cutaneous delayed type hypersensitivity (DTH) and antibody responses to a hapten, oxazolone (OXA). Moreover, in vitro proliferative response to Concanavalin A (Con A) and production of interleukin 2 (IL-2) were severely depressed in aged NZB/W mice. In transfer experiments we show that a single i.p. injection of non-immune mononuclear spleen cells from young NZB/W mice to old diseased syngeneic recipients restores DTH reactivity and increases the antibody response to OXA. This effect is a CD4(+)-dependent process since the restoration of T-cell responses was abrogated upon elimination of CD4+ donor T cells. Overall, our results indicate that limited numbers of CD4+ T cells display substantial immunoregulatory properties reversing the state of anergy in autoimmune NZB/W mice.

Aging↗

PubMed1991

Experimental Staphylococcus aureus arthritis in mice.

Staphylococcus aureus arthritis is usually caused by bacteremia and is highly destructive. Controlled studies on septic arthritis in humans are difficult to perform, because the time of onset of the infection is unknown. Animal models of bacterial arthritis make it possible to control important variables in experimental studies. We present a mouse model of S. aureus arthritis in which the intravenous administration of 10(7) cells of S. aureus LS-1 induced arthritis or osteitis or both within 3 weeks in 80 to 90% of the mice. Signs of arthritis emerged within the first few days after the injection. An interesting finding was that the S. aureus strain used in this study binds bone sialoprotein, a glycoprotein known to be specifically localized to bone tissue. This new model of S. aureus arthritis enables the study of the kinetics of joint destruction and the host-bacterium relationship as well as therapeutical approaches to septic arthritis and osteomyelitis.

Animals↗

PubMed1991

Peripheral denervation suppresses the late phase of delayed-type hypersensitivity.

The impact of peripheral denervation on antigen-specific immune responses was analysed on the B and T cell levels. Delayed-type hypersensitivity (DTH) response to sheep red blood cells (SRBC) or oxazolone was used in mice as a model system of in vivo T cell reactivity. Serum antibody levels to SRBC, measured by an enzyme-linked immunosorbent assay (ELISA), were evaluated to analyse the B cell response. The effect of peripheral denervation on immune responsiveness was studied both at the point of sensitization and elicitation. The results show that peripheral denervation significantly suppresses the local DTH response. The late, inflammatory phase but not the early phase of the DTH reaction was reduced after denervation (p less than 0.01). The DTH suppression by denervation was similar irrespective of whether the neurectomy was performed 1 or 4 weeks prior to sensitisation. Even in the contralateral limb, with intact innervation, the inflammatory DTH reactivity was decreased. We believe that this phenomenon might be due to abrogation of the reflex arch since the denervation procedure did not give rise to a significant systemic downregulation of DTH. Also, peripheral denervation significantly suppressed footpad swelling induced by local administration of cholera toxin, a potent phlogistic compound. The antibody response against the same immunogen was not influenced by denervation. Our results suggest that denervation of a mixed peripheral sensory/motor nerve abrogates the formation of both T cell-dependent and independent inflammatory responses.

Animals↗

PubMed1991

Involvement of macrophages and dendritic cells in synovial inflammation of collagen induced arthritis in DBA/1 mice and spontaneous arthritis in MRL/lpr mice.

Type II collagen induced arthritis (C1A) is an antigen-specific and T-cell dependent autoimmune disease in which the time course of disease is known. Arthritis is induced with type II collagen (CII) immunization, but can also be induced with passive transfer of anti-CII antibody containing syngenic serum and with local administration of gamma interferon. In the present study we analysed the spectrum of inflammatory cells appearing in the arthritic joints. Three phases of the disease process could be defined: 1) Early infiltration of T cells and appearance of class II expressing macrophages in the synovial lining layer 2) Profound infiltration of granulocytes and oedema formation and 3) Pannus formation containing activated macrophages, granulocytes, T cells and dendritic cells. At this severe destruction of cartilage and bone beginning from the marginal zone was seen. In contrast, joints from spontaneously arising arthritis in MRL lpr/lpr mice showed no granulocytes or T cells, sparse expression of class II but relatively uniform appearance of C3bi-receptor+, Fc-receptor+ and MOMA2+ synovial cells.

Animals↗

PubMed1991

Increased systemic T-lymphocyte reactivity in patients with established stroke.

We have analyzed the impact of stroke with subsequent hemiparesis and sensory loss on systemic in vivo and in vitro mediated immune functions. Delayed-type hypersensitivity (DTH) reaction to purified protein derivate (PPD, tuberculin), evaluated on the non-paretic side, was used as an in vivo measure of systemic antigen specific T-cell reactivity. Subcutaneous immunization with influenza vaccine was employed to analyse T-cell dependent B-cell function. The influence of stroke on T-cell function in vitro was studied by proliferative responses to PPD and Concanavalin A. Twenty five out of 54 (46%) stroke patients tested displayed positive DTH reaction to PPD. In contrast, only 24% of age matched controls displayed positive DTH reaction (p < 0.05). There was a good correlation between in vivo and in vitro reactivity to PPD. Consequently, peripheral blood mononuclear cells in 50% of stroke patients but only in 20% of matched controls showed proliferative response in vitro to PPD. Immunization of stroke patients and controls with influenza vaccine, a T-cell dependent B-cell antigen, raised equal antigen-specific serum IgG, IgA and IgM antibody responses in both study groups. We conclude that (a) stroke enhances systemic antigen-specific T-cell reactivity in vivo and in vitro, and (b) stroke has no significant effect on antigen-specific B-cell responses.

Aged↗

PubMed1991

Analysis of the genetic encoding of oestradiol suppression of delayed-type hypersensitivity in (NZB x NZW) F1 mice.

Oestrogen (E2) has been suggested to be responsible for the female preponderance for systemic lupus erythematosus (SLE) and for exacerbations of disease during pregnancy. In lupus-prone (NZB x NZW) F1 (NZB/W) mice, sex hormones also influence disease progression, thus long-term treatment of NZB/W mice with high doses of oestradiol increases the mortality in immune-complex mediated disease. We have previously demonstrated that E2 suppression of delayed-type hypersensitivity (DTH) to oxazolone (OXA) in NZB/W mice is inherited from the healthy NZW (H-2z) and not from the autoimmune NZB (H-2d) parental strain. In this paper we have analysed the influence of E2 on DTH and antibody responses to OXA in backcrosses of NZB/W mice and the NZB and NZW parental strains. Suppressed DTH was found in 15/16 (94%) of female (NZB/W x NZW) F1 (NZB/W/W) mice treated with E2. In contrast, only 32/36 (51%) of (NZB/W x NZB)F1 (NZB/W/B) mice treated with E2 displayed suppressed DTH reactivity. These two findings are compatible with a single, rather than multiple, dominant gene inherited from the NZW strain encoding for E2-mediated suppression of DTH in NZB/W mice. FACS analysis, using a monoclonal antibody recognizing the H-2z but not the H-2d locus, identified the H-2 expression (H-2dd and H-2dz) of the NZB/W/B backcrosses and revealed that E2 suppression of DTH is not linked to the H-2 haplotype of the backcrosses. Furthermore, E2 treatment of NZB/W/W mice, but not of NZB/W/B mice, significantly enhanced the serum levels of anti-OXA antibodies of both IgG and IgM classes. Based on our results it is tempting to speculate whether similar genetic factors for E2 sensitivity of the immune system may be of importance for the female predominance of human SLE.

Animals↗

PubMed1990

Immunization of humans with polysaccharide vaccines induces systemic, predominantly polymeric IgA2-subclass antibody responses.

Ig class- and IgA subclass-specific immune responses to protein and polysaccharide Ag were studied in serum, external secretions, and at the single cell level in peripheral blood of systemically immunized adults. Immunization with tetanus toxoid induced predominantly IgG antibody responses in serum and in the PBMC. The IgA antibody response was low, and was mostly of the IgA1 subclass. In contrast, immunization with polysaccharide Ag (Haemophilus influenzae type b, Neisseria meningitidis serogroup A, C, Y, W-135, and Streptococcus pneumoniae capsular polysaccharides) elicited a major IgA response predominantly of the IgA2 isotype. Analysis of the molecular forms of secreted IgA antibodies indicated that polymers were produced early after immunization, irrespective of the nature of the Ag. When compared with serum antibody and to PBMC cell responses, systemic immunization with polysaccharides induced a minor salivary response dominated by IgG and IgM antibodies. In contrast, the presence of antipolysaccharide antibodies in bile, irrespective of their isotype, paralleled the serum response 14 days after the immunization with polysaccharide Ag. These results suggest that biliary Ig were mostly derived from serum. Different patterns of the expression of MHC class II Ag on T cells, B cells, and monocytes during the course of immunization with protein or polysaccharide Ag were observed: whereas protein Ag induced a high frequency of HLA-DP- and HLA-DR-expressing cells early in the course of immunization, polysaccharide vaccines elicited low and protracted increases of HLA-DP+ T cells. Polysaccharide vaccine covalently coupled to a protein carrier induced a higher frequency of antipolysaccharide antibody-secreting cells in peripheral blood and increased the IgG to IgA ratio among polysaccharide-specific antibody-secreting cells.

Adult↗

PubMed1990

Outbreak of spontaneous staphylococcal arthritis and osteitis in mice.

Staphylococcus aureus is the most common bacterial species found in association with nongonococcal bacterial arthritis in humans. We present here the first description of spontaneous bacterial arthritis and osteitis in mice. Clinically, the most obvious findings were swelling and/or ankylosis of hindpaws and nodose changes of the tail. The prevalence of arthritis and osteitis ranged from 0% to greater than 50% of the mice studied, depending on the mouse strain. The most prominent histopathologic feature of the arthritis was hypertrophy of the synovial tissue and destruction of cartilage and underlying bone. Most of the S aureus-infected mice displayed an identical phage type, which was also the only S aureus phage type found in skin isolates from clinically healthy mice. However, a few S aureus isolates were not typeable, indicating that an additional strain(s) might cause bacterial arthritis in mice.

Animals↗

PubMed1990

Differential effects of captopril and enalapril, two angiotensin converting enzyme inhibitors, on immune reactivity in experimental lupus disease.

We have previously demonstrated that Captopril, an inhibitor of angiotensin converting enzyme (ACE), ameliorates experimental systemic lupus erythematosus in inbred MRL lpr/lpr (MRL/l) mice. In contrast, Enalapril, another ACE inhibitor with antihypertensive properties but lacking a thiol group, did not show similar beneficial effects. To better understand the mode of action of captopril in the autoimmune disease we have evaluated its immunomodulatory properties with special emphasis on antigen-specific and polyclonal B- and T-cell activation. The results obtained strongly suggest that Captopril exerts its immunomodulatory effects through stimulation of T-lymphocytes.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice.

The influence of oestrogen on the lupus disease in MRL/l mice has been investigated. Adult, castrated male and female MRL/l mice were administered with s.c. injections of 3.2 micrograms of 17 beta-oestradiol twice a week. The results clearly demonstrate that a relatively small dose of oestrogen is a potent accelerator of the lupus disease in this mouse strain. Thus, administration of oestrogen accelerates glomerulonephritis, lymphoproliferation and mortality. Our results also indicate that oestrogen exerts a dual effect on the immune system of MRL/l mice by depression of antigen-specific and mitogen-induced T cell responses as well as enhancement of polyclonal B cell activation and autoantibody formation. In addition, even short-term administration of oestrogen in the preclinical phase of the disease resulted in long-lasting effects as evaluated by reduced longevity and aggravation of renal disease.

Animals↗

PubMed1990

Intra-articular immunization induces strong systemic immune response in humans.

There is no information available about immunological interactions between the synovial tissue compartment and systemic immunity in health and in disease. The aim of the present study was to evaluate effects of intra-articular immunization on the systemic immune responses in humans. Control subjects were immunized with the same dose of immunogen subcutaneously. Peripheral blood lymphocytes were analysed by spot-ELISA with respect to numbers of immunoglobulin-producing cells and antigen-specific antibody-secreting cells before and 1 week after immunization. Serum and salivary antibody levels were measured by an ELISA before and 14 days after the antigenic exposure. In addition, serum levels of interleukin-6 (IL-6) were analysed before and after immunization. The results indicate that the influenza virus antigen deposited in the joint space induces strong systemic antibody response of IgG, IgA and IgM classes. This response is significantly higher (P less than 0.05) than that of control subjects immunized subcutaneously. In contrast, no significant differences were detected between intra-articularly and subcutaneously immunized subjects with respect to mucosal immune responses. Increased serum levels of IL-6 were observed 1-2 weeks after the vaccination in both experimental groups. We conclude that human joints possess very efficient antigen-presenting properties enhancing systemic B cell reactivity.

Adult↗

PubMed1990

Expression of heterozygous lpr gene in MRL mice. II. Acceleration of glomerulonephritis, sialadenitis, and autoantibody production.

Recently we showed that not only homozygous MRL lpr/lpr mice but also heterozygous MRL +/lpr mice display defective antigen- and mitogen-driven T-cell responses as well as polyclonal B-cell activation compared with congeneic MRL +/+ mice. In this study we examined the impact of the heterozygous lpr gene on organ pathology in kidneys, joints, and salivary glands, as well as serum levels of immunoglobulins and autoantibodies in young and old MRL mice. Only 1 out of 17 heterozygous lpr-bearing MRL mice developed clinically overt renal disease with significant proteinuria and haematuria during the first year of life. However, examination of Ig and C3 deposits in glomeruli of kidneys from these mice revealed that the expression of the heterozygous lpr gene in MRL mice accelerates glomerulonephritis. In addition, histological examination of the submandibular salivary glands showed an increased focus score in heterozygous MRL mice at 4-5 months of age compared with that of matched congeneic +/+ mice. In contrast, no signs of arthropathy were registered in the heterozygous lpr-bearing MRL mice. Heterozygous MRL mice displayed an expanding lymphoid system as evaluated by significantly increased spleen and lymph node weights compared with those of matched MRL +/+ mice. Further evidence for immunomodulatory properties of the heterozygous lpr gene was obtained when analysing serum levels of IgG, IgM, and autoantibodies. Thus, heterozygous MRL +/lpr mice produced significantly higher levels of both Ig and autoantibodies than matched MRL +/+ mice. We conclude that the expression of the heterozygous lpr gene in MRL mice results in acceleration of the autoimmune process, giving rise to precocious clinical disease.

Age Factors↗