Haematopathology of 'Sjögren-mice': histopathological changes in spleens after semiallogeneic cell transfer.

Haematopoietic transplantation chimeras may be readily produced in adult mice, using F1-hybrids of selected inbred strains as recipients and mice from one of the parental strains as donors. We transplanted spleen cells from BALB/c donors into nonirradiateded F1-hybrids of BALB/c and CBA/H-T6. Both female and male recipients developed a primary Sjögren's syndrome-like exocrinopathy without signs of kidney disease. At long-term follow-up, 7(1/2) months after cell transfer, lymph nodes were enlarged, and spleens were diminished and irregular in shape. In general, changes in haematopoietic organs were more prominent in males. The results verify that although hybrid mice of either sex develop glandular manifestations comparable with primary Sjögren's syndrome, when the immune system is stimulated by semiallogeneic immunocytes, the evoked reactions in haematopoietic tissues show gender difference.

Sex-specific patterns of spleen recolonization in semiallogeneic "Sjögren-mice".

"Sjögren-mice" were produced by the transfer of two entire spleen equivalents of cells from parental strain mice to non-irradiated, adult F1 hybrids. The recipients developed an autoimmune exocrinopathy resembling primary Sjögren's syndrome. Since donor and host mice are haploidentical, no new antigens are introduced into the recipients. Donor cells may react against recipient antigens, eliciting a graft versus host (GVH) reaction. The origin of spleen cells was investigated by flow cytometry, using antibodies against murine MHC antigens. The results showed different colonization patterns: spleens of female recipients, grafted with cells from female donors, were almost completely colonized by donor type cells, whereas spleens of male recipients, grafted with either male or female cells, showed partial or complete colonization by donor type cells. The results suggest that the sex of both donor and host influences cellular reactions in lymphohaemopoietic chimeras.

What mechanisms control neoteny and regulate induced metamorphosis in urodeles?

The Mexican axolotl, like a number of other urodele species, is an obligatory neotene, completing its full life cycle without metamorphosis. Metamorphosis can be induced with thyroid hormone, thyroid stimulating hormone, or stimulation of hypothalamic neurons. Thus, neoteny represents a deviation from the standard course of amphibian ontogeny, affecting the thyroid axis at one or more levels. Analysis of the thyroid axis at strategic ontogenic stages and after completed neotenic development suggests that there are a number of deviations, and that the deviations may be temporal and/or quantitative in nature. A surge of thyroxine secretion occurs early in larval life but does not lead to metamorphosis, apparently because the enzyme which deiodinates thyroxine to the active form, triiodothyronine, is not yet present. Later in ontogeny, activity in the thyroid axis is low. Hormone treatment can reactivate the thyroid axis at all levels, but some singularities remain. Inhibition at central nervous or peripheral levels may be involved in axolotl neoteny.

Effect of induced metamorphosis on the immune system of the axolotl, Ambystoma mexicanum.

Metamorphosis was induced in neotenic axolotls by immersion of the animals in a solution of thyroid hormone. Hematology of the axolotls was examined before, during, and after metamorphosis. There was a transient decrease in numbers of certain white blood cells during metamorphic climax and a permanent shift in the pattern of circulating cells. The eosinophilic granulocyte was the dominating leukocyte type in neotenes and in metamorphosing animals up to midclimax. Lymphocytes and neutrophilic granulocytes (polymorphs) significantly decreased during midclimax. In postmetamorphic axolotls, lymphocytes and polymorphs predominated. The observed decrease of some leukocytes in metamorphosing animals accords with a transient immunosuppression at metamorphic climax. Metamorphosed axolotls showed a humoral immune response (increase in circulating plasma cells) after repeated antigen challenge, whereas neotenic axolotls did not. Alterations in both cellular and humoral immunity are suggested to occur in both young and adult axolotls following experimental induction of metamorphosis.

Histopathological changes in exocrine glands of murine transplantation chimeras. I: The development of Sjögren's syndrome-like changes secondary to GVH induced lupus syndrome.

Sjögren's syndrome (SS) is a connective tissue disease characterized by general affection of exocrine glands. The three main components of SS are: dry eyes, dry mouth, and other connective tissue disease. When only two of these, dry eyes and dry mouth, are present, the disease is designated primary SS. In the presence of the third component, most commonly SLE or RA, with one or both of the two first components the disease is designated secondary SS. In murine transplantation chimeras, we have demonstrated the development of both primary and secondary SS depending upon the mouse strains used. We transferred large numbers of viable leucocytes from homozygotic donors to heterozygotic recipients. When DBA/2 mice were used as donors, a full-developed SLE-syndrome, with autoantibodies against native DNA, nuclear antigens, and red blood cells was observed. We found immune deposits in skin ("lupus band") and kidneys, immune complex glomerulonephritis (ICGN), proteinuria, ascites, and hepatosplenomegaly. In later stages, we found a generalized dacryoadenitis. In the kidneys we found interstitial nephritis, and occasionally "half-moon" nephritis. In skin, immune deposits were demonstrated in intercellular spaces. These findings are similar to those found in patients with Sjögren's syndrome secondary to SLE. The murine transplantation chimera is therefore an experimental model for spontaneous autoimmune diseases.

Histopathological changes in exocrine glands of murine transplantation chimeras. II: Sjögren's syndrome-like exocrinopathy in mice without lupus nephritis. A model of primary Sjögren's syndrome.

Autoimmune reactions are evoked in hybrid mice after induction of a chronic graft-versus-host reaction by transfer of viable leucocytes from one of the parental strains to non-irradiated F1 recipients. We have previously demonstrated an SLE-like syndrome early in the reaction, with an additional Sjögren's syndrome-like glandular affection occurring later. In this study, we used Balb/c mice as donors and Balb/cxCBA/H-T6 F1 hybrids as recipients. We found serum autoantibodies characteristic of SLE after 9 weeks but not after 20 weeks. No clinical signs of disease were seen at any time. After prolonged studies (5 months), we found heavy inflammation in Harderian, salivary, and tear glands. All animals survived the entire length of the experiment without signs of renal failure. The pathological manifestations: lymphocytic infiltration of exocrine glands, and enlargement of lymph nodes, are similar to those seen in patients with Sjögren's syndrome. This murine transplantation chimera may be a useful experimental model for primary Sjögren's syndrome.