Pregnancies modulate B lymphopoiesis and myelopoiesis during murine ageing.

We recently reported that pregnancy affects age-related changes in the distribution of lymphoid and macrophage populations in the spleen of C57Bl/6 mice. In the present study, we examined the influence of pregnancies on the generation of various developmental B-cell subsets and granulocyte/macrophage lineage cells during murine ageing. Using flow cytometry, changes in lymphoid (mature and early B-cell precursors: B220high, B220low, surface immunoglobulin M (sIgM) mu chain +/-) and myeloid (monocyte/macrophage Mac-1/CD11b, granulocyte Gr-1/Ly-6G) compartments were monitored in the bone marrow of young (2 months) and 15- and 23-month-old mice including male, multiparous and virgin female mice. Pregnancies delayed the age-related decline in murine B lymphopoiesis and maintained B-cell reserve capacity during ageing. We also found an increased production of myeloid cells induced by pregnancies at middle (15 months) and advanced (23 months) ages. This comparative study provides new information on changes in marrow lymphopoiesis and myelopoiesis with age. Our data emphasizes that the onset, magnitude and kinetics of age-related changes in the haematopoietic marrow are parity dependent. These changes could influence the incidence of age-related diseases and may account for the greater longevity of females.

[Aging and the immune system. Experimental aspects]. / Vieillissement et système immunitaire. Quelques aspects expérimentaux.

So far no comparative studies have been conducted to know whether physiological influences related to sex hormonal differences affect the age-related changes of the immune system. The aim of this study was to investigate whether pregnancies and sex influence the age-related changes in the peripheral lymphoid compartment and functions of T cells in mice. Using flow cytometry, we examined changes in (Thy1.2+) T cells, (B220+) B cells and (CD11b/Mac-1+) macrophages in the spleen of multiparous and virgin females and males at 2, 8, 15 and 23 months of age. The development of naive (CD44low) and memory (CD44high) cells were investigated in CD4+ and CD8+ T cell subsets. To analyze the age-related changes in functions of T cells, we examined the secretion of some T cell immunoregulatory cytokines (IL-2, IL-4, gamma-interferon and GM-CSF) of in vitro Concanavalin A-activated spleen cells of C57BL/6 mice. Both short term (8 months) and long term (15-23 months) effects of pregnancies were obvious in the age-related changes of the immune system. Short term effect included delayed appearance of memory CD4+ cells and the preserved IL-2 production. At eight months, shortly after pregnancies, both parameters were higher in multiparous females. Later effects of pregnancies were evidenced by a higher level of macrophages (Mac-1+) than in other groups throughout life. The increased gamma-interferon, IL-4 and GM-CSF productions appeared earlier, at 15 months, IL-4 and GM-CSF levels remained higher in multiparous females than in virgin females and males in late adulthood. Sex differences were also noticed: males exhibited lower macrophage levels after one year and gamma-interferon secretion capacity than females in late life. This study underlines that the onset, magnitude and kinetics of the age-related changes in the distribution of immune cells and T cell functions are parity- and sex-dependent. These changes may influence the incidence of age-related diseases and may explain the greater longevity of women, especially the multiparous ones.

Sex and parity modulate cytokine production during murine ageing.

We have previously shown that physiological hormone differences related to pregnancy or sex affect the age-related distribution of mononuclear cell populations during murine ageing. To determine whether such changes are involved in the age-related changes in functions of T cells, we examined the secretion of major T cell immunoregulatory cytokines (IL-2, IL-4, interferon-gamma (IFN-gamma), IL-3, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) of in vitro concanavalin A-activated spleen cells of C57B1/6 mice. The study included multiparous and virgin females and males at 2, 8, 15 and 23 months of age. Short-term effects of parity (8 months) were evidenced by the decrease of IFN-gamma and the preserved IL-2 production in multiparous females (8 months), while IFN-gamma was unchanged and IL-2 decreased in virgin mice. The increase in IL-4 production appeared earlier in multiparous females (15 months) than in virgin mice (23 months). The increase in IL-4/IFN-gamma and IL-4/IL-2 ratios at 8 and 15 months, respectively, in multiparous females, suggests that pregnancy modifies the Th1/Th2 equilibrium. In late adulthood (15 months), IL-6 and GM-CSF production was higher in multiparous females than in virgin males or females. Sex differences were also noticed: IFN-gamma secretion capacity was lower in males than in females during ageing. This study underlines that the onset, magnitude and kinetics of the age-related changes in cytokine production are parity- and sex-dependent. These changes probably influence the incidence of age-related diseases and may explain the greater longevity of females.

[Cat scratch disease and associated infections]. / Maladie des griffes du chat et infections associées.

Cat scratch disease (CSD) was first described in France by Debré et al. in 1950, yet the causative bacterial agent of CSD remained obscure until 1992, when Bartonella (formerly Rochalimaea) henselae was implicated in CSD by serological and microbiologic studies. B. henselae had been linked initially to bacillary angiomatosis (BA), but also bacillary peliosis, relapsing bacteremia and endocarditis. Cats are healthy carriers of B. henselae and B. clarridgeiae, and can be bacteremic for months to years. Cat to cat transmission of the organism involves the cat flea in absence of direct contact transmission. Present knowledge on the etiology, clinical features and epidemiological characteristics of cat scratch disease/bacillary angiomatosis are presented.

[Helicobacter infections of man and of domestic carnivores: comparative data]. / Hélicobactérioses de l'homme et des carnivores domestiques: quelques données comparatives.

The role of Helicobacter pylori in generating of the chronic gastritis and in the maintaining of the gastroduodenal ulcerous disease, has been a major medical discovery of these past years in human gastroenterology. More recently in Man, studies have showed that the gastric tumours (adenocarcinoma, lymphoma) are epidemiologically associated with the H. pylori infection. Although the H. pylori infection is the one of the most frequent in the word, the epidemiologic and ecologic aspects of this infections are still not very well known. Thanks to phylogenic studies using the new molecular biology techniques and to fundamental experimental studies, we know more about helicobacteria in domestic carnivores as well as their morphologic characteristic, their taxonomia and more importantly details concerning their ecological niche. Few clinical studies have been made to this day, but the ones that have been undertaken are interesting in confirming the extensive prevalence of Helicobacter infections in domestic carnivores and in underlining their role in the genesis of the inflammatory gastropathies observed in these species. Recent observations have demonstrated the ubiquitous character of these helicobacteria by showing their presence in the stomach of man, dogs and cats. This ubiquitous character has led some scientists to consider the potential zoonotic risk of the human infection by Helicobacter heilmannii, felis or pylori. Finally, the Helicobacter infection of animals seems to be an interesting model not only in the study of the affections caused by these bacteria, but also in the elaboration of a future vaccine against the H. pylori infection in man.

Stimulatory effects of polar glycopeptidolipids of Mycobacterium chelonae on murine haematopoietic stem cells and megakaryocyte progenitors.

The effects of polar glycopeptidolipids of Mycobacterium chelonae (pGPL-Mc) on haematopoietic stem cells and on megakaryocyte progenitors in bone marrow (BM) and spleen were investigated in mice. We studied the in vivo spleen colony-forming ability and marrow repopulating ability of pGPL-Mc by assays of colony-forming units-spleen (CFU-S). The number of CFU-S was increased in BM when both donors and recipients were treated with pGPL-Mc. In contrast, a single treatment of donors induced enhancement of spleen CFU-S. The number of pre-CFU-S was not significantly increased by pGPL-Mc injection. Megakaryocyte (Meg) progenitors were determined in vitro with a quantitative cultural analysis of bone marrow and spleen cells in agar in the presence of spleen-conditioned medium. A statistically significant increase in BM and spleen CFU-Meg was observed two days after the last administration of pGPL-Mc. This experiment points out the ability of pGPL-Mc to induce substantial stimulation of megakaryocytopoiesis and slight proliferation of stem cells in BM, but which is more pronounced in spleen. This molecule therefore appears to be a potential adjuvant of chemo- and radiotherapy in order to palliate the cytotoxic side effects of these cancer therapeutic modalities.

Effects of polar glycopeptidolipids of Mycobacterium chelonae (pGPL-Mc) on haematopoietic regeneration and resistance to infection of sublethally irradiated mice.

The influence of polar glycopeptidolipids of Mycobacterium chelonae (pGPL-Mc) treatment on the reversal of irradiation-induced leukopenia (granulocytopenia, monocytopenia) and thrombocytopenia and its ability to protect mice against lethal infections were investigated in this study. The administration of pGPL-Mc to irradiated mice significantly accelerated the recovery of leukocyte and thrombocyte numbers in the peripheral blood. Granulocytes and monocytes were the principal cells of the leukocyte population that responded to the potent stimulus of this product. The reversal of granulocytopenia and monocytopenia in treated mice was achieved on day 14 and reached a peak value on day 20. Responses in mice receiving 100 mg/kg of pGPL-Mc was about 40-fold compared to controls and about 4-fold compared to the rhG-CSF-treated group. Normal levels of thrombocytes were reached by day 17 in mice treated with 100 mg/kg and by day 20 in those receiving 25 mg/kg of pGPL-Mc. The administration of pGPL-Mc to mice with irradiation-induced granulocytopenia was characterized by highly significant protection of these animals against lethal Klebsiella pneumoniae or Escherichia coli infections. Therefore, pGPL-Mc appears to possess a considerable potential for improvement of the outcome of radiotherapy and may contribute to the successful avoidance of irradiation-induced toxicities.

Effects of polar glycopeptidolipids of Mycobacterium chelonae (pGPL-Mc) on granulomacrophage progenitors.

Effects of polar glycopeptidolipids of Mycobacterium chelonae (pGPL-Mc) in the in vivo stimulation of haematopoietic growth and differentiation of murine bone marrow and spleen cells was investigated in this study. Progenitors were determined with a quantitative cultural analysis of bone marrow and spleen cells in methylcellulose using rmGM-CSF and rmIL3. Injection of pGPL-Mc produced a significant time-related increase in the number of bone marrow and spleen CFUs. pGPL-Mc treatment, in particular, increased the number of bone marrow and splenic CFU-GMs, CFU-Gs and CFU-Ms during and after three intraperitoneal administrations. The greatest myeloid stimulation of bone marrow CFU-GMs, CFU-Gs and CFU-Ms was observed between days 7 and 14, with maximal values on days 12 and 14. Highly significant stimulation of splenic CFU-GMs, CFU-Gs and CFU-Ms was observed between days 7 and 10 with maximal values on day 10, while the initial stimulation of these progenitors was observed starting from day 1 in bone marrow and day 7 in spleen. These effects of pGPL-Mc were associated with an increase in granulocyte, monocyte and thrombocyte counts in the peripheral blood. Granulocyte and monocyte counts remained high up until day 12, while those of thrombocytes were prolonged until day 18. May-Grünwald-Giemsastained colony samples and differential white blood cell counts demonstrated that the granulocyte population is composed almost entirely of neutrophils. pGPL-Mc is therefore a broad-spectrum haematopoietic growth factor with a highly promising application in the reversal of chemotherapy- and/or radiotherapy-induced myelo-suppression.

[Activity of polar glycopeptidolipids from Mycobacterium chelonae in the reversal of chemically induced leukopenia in mice]. / Activité des glycopeptidolipides polaires de Mycobacterium chelonae sur la restauration d'une leucopénie chimioinduite chez la souris.

Intraperitoneal administration of polar glycopeptidolipids extracted from Mycobacterium chelonae (GPLp-Mc) has led to reversal of Doxorubicin-induced leucopenia in a manner comparable to that effected by GM-CSF administered in a dose of 100 IU (2.5 micrograms/kg). The mode of action and the toxicity of this product are being studied. Results obtained on the mouse indicate that it would be worthwhile to undertake tests in man aimed at studying the effect of GPLp-Mc on chemotherapy- and radiotherapy-induced leukopenias, once toxicological studies have been carried out.

[Cat retroviruses and human retroviruses: elements of comparison]. / Rétroviroses du chat et rétroviroses de l'homme: éléments de comparaison.

Following emotional head-lines of certain articles in the press, making believe that the cat could be susceptible to the AIDS virus, the authors present elements of comparison between principal feline retroviruses (the feline leucosis virus and the feline immunodeficiency virus) and the two human immunodeficiency viruses (HIV). The feline leucosis virus in differentiated from the human and the feline immunodeficiency viruses by its virological, pathological and epidemiological characteristics. Being close to the AIDS virus in the taxonomy of retroviruses, the feline immunodeficiency virus (FIV) presents a number of similarities with the HIV. Therefore, the FIV could give rise to interests in its use as a model in the study of AIDS. Whatever the factors of resemblances may be, there are no elements of present knowledge in favor of an inter-species contamination (cat-man); on the contrary, these viruses demonstrate a marked species specificity.

Immunomodulatory properties of a strain of Mycobacterium chelonae. I. Mouse lymphocyte responses in vitro.

Immunomodulatory properties of a strain of live Mycobacterium chelonae (Mch) was investigated in an in vitro lymphocyte transformation system. Murine splenocyte activation by this bacterium was characterized by polyclonal lymphoproliferative responses in a dose dependent fashion. Optimal doses ranging from 20 to 80 micrograms of Mch (wet weight) per ml of cell suspension induced a very significant mitogenic effect. Higher doses (100 micrograms) of Mch manifested a decreased rate of tritiated thymidine ([3H] TdR) uptake whereas responsiveness of splenic lymphocytes to lower doses (0.156 microgram) was not modified. Contrary to the splenocyte responses activation of murine thymocytes by this mycobacterium is characterised by a decreased proliferation as compared to the background count of unstimulated cells. Simultaneous addition of Mch with optimal doses of Concanavalin A (Con A) and Phytohemaglutinin (PHA) potentiated polyclonal mitogenic responses of murine splenocytes to these two lectins. However, proliferation of these lymphocytes to Lypopolysaccharide (LPS) induction was not modified. BALB/C and DBA/2 spenocytes were found to be more responsive to stimulation by this Mycobacterium as compared to those of C3H/Ou and to a lesser degree to those of C57BL/6 mice.

[Brucella and modification of the host response to bacterial and viral infection. Effect of the S-R variation]. / Brucella et modifications de la reponse de l'organisme à des infections bacteriennes et à une infection virale. Influence de la variation S-R

Within the framework of a study on the immunostimulant properties of Brucella abortus and of its extracts, we have investigated the protective activity on infection of mice by Klebsiella pneumoniae and on Charlotte Friend's leukemia, of inactivated Brucella abortus and brucella lysates by ultrasound. The injection of inactivated B 19 R preparations and their lysates three days before infection by klebsiella has allowed to protect mice against a large number of DL50 (100 and 1000 in certain cases). To determine the role of the surface antigen in this type of immunostimulant, the activity of the B 19 R inactivated preparations has also been examined. It appears that the protection obtained by the injection on day J + 3, in relation to the infection, does not depend on the presence of the complete surface antigen, while the long term effect seems to be more dependent on this. The development of Charlotte Friend's leukemia has been favourably influenced by the previous injection of B 19 S or inactivated B 19 R. Immunotherapy on days J + 1 or J + 3 gave encouraging results with B 19 R, but facilitation with B 19 S. These results confirm the immunostimulant activity of brucella which has already been reported by ourselves and by other authors.