Chronic graft-versus-host disease-like autoimmune disorders spontaneously occurred in rats with neonatal thymus atrophy (original) (raw)
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Graft versus Host Disease in the Bone Marrow, Liver and Thymus Humanized Mouse Model
PLoS ONE, 2012
Mice bearing a ''humanized'' immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice). The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/cc 2/2 ) delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.
Journal of Experimental Medicine, 1984
We studied the alloreactive properties of donor T cells obtained from F1 mice that had recovered from the allosuppression of acute graft-vs.-host disease (GVHD) and showed mild symptoms of chronic GVHD, i.e., so-called secondary chronic GVHD. To this end, we used (B10 x DBA/2)F1 mice that had been injected with 10(8) B10 spleen cells 100-150 d previously. Such GVHD F1 mice were repopulated by lympho-hematopoietic cells of donor (B10) origin, which exhibited split tolerance towards the host: Whereas F1-specific donor T helper (Th) cells as well as T cells proliferating in the mixed lymphocyte reaction were readily demonstrable, F1-specific T suppressor (Ts) and T killer (Tk) cells were not, or were hardly, detectable; responses against third-party alloantigens were normal. Upon adoptive transfer to nonirradiated secondary recipients, the B10 cells obtained from the repopulated GVH F1 mice induced F1-specific enlargement of the draining popliteal lymph node and enhancement of the IgG ...
Biology of Blood and Marrow Transplantation, 2013
Chronic graft-versus-host disease (cGVHD) is a significant roadblock to long-term hematopoietic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multiorgan pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. Starting at time points generally later than 100 days post-transplantation, the mice developed signs of illness, including multiorgan cellular infiltrates containing human T cells, B cells, and macrophages; fibrosis in sites such as lungs and liver; and thickened skin with alopecia. Experimental manipulations that delayed or reduced the efficiency of the HSC engraftment did not affect the timing or progression of disease manifestations, suggesting that pathology in this model is driven more by factors associated with the engrafted human thymic organoid. Disease progression was typically accompanied by extensive fibrosis and degradation of the thymic organoid, and there was an inverse correlation of disease severity with the frequency of FoxP3 þ thymocytes. Hence, the human thymic tissue may contribute T cells with pathogenic potential, but the generation of regulatory T cells in the thymic organoid may help to control these cells before pathology resembling cGVHD eventually develops. This model thus provides a new system to investigate disease pathophysiology relating to human thymic events and to evaluate treatment strategies to combat multiorgan fibrotic pathology produced by human immune cells.
Development of T cells in SCID mice grafted with fetal thymus from AKR mice or F344 rats
European Journal of Immunology, 1993
To examine the development of Tcells within an allogeneic or xenogeneic environment, we engrafted the fetal thymus from AKR mice or F344 rats under the kidney capsule of SCID mice (mTG and rTG mice). Tlymphopoiesis developed in SCID mice 2 months after transplantation, although the ratio of CD4/CD8 in both experimental groups was different from that of normal control. T cells in mTG mice did not show in vim proliferation or cytotoxicity against either host-type C.B-17 (H-2d) or donor-type AKR (H-2k) cells, while they exerted potent activities against third-party B10 (H-2b) cells. In contrast, T cells in rTG mice exhibited proliferation against both host-type C.B-17 and donor-type F344 rat cells. Consistently, graft-vs. -host disease symptoms developed in these mice and histological examination showed impressive infiltration of lymphocytes into the skin or into the mucosal layers of the stomach. Activated state of T cells in rTG mice was also evidenced by the positive expression of interleukin-2 receptor. Taken together, fetal thymus appears to contain progenitor cells which are sufficient for in vivo reconstitution of T lymphopoiesis, but species-specific environment is important for the induction of tolerance. In mTG mice, Vp6+ T cells reactive to donor Mls" determinants and Vf33+ T cells reactive to host MlsC determinants were deleted, suggesting that tolerance was regulated mainly by clonal deletion. By contrast,Vpll+ T cells reactive to Mlsf determinants were not deleted possibly due to the lack of their ligands.
Blood, 2015
During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus, implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that medullary thymic epithelial cells expressing the autoimmune regulator (Aire(+)mTEC(high)) are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC(high) cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during aGVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC(high) cells. Our data therefore indicate that a functional compromise of the medullary mTEC compartment may link alloimmunity to the development of autoimmunity...
Pathogenesis of Autoimmunity After Xenogeneic Thymus Transplantation
The Journal of Immunology, 2003
Thymus transplantation is a promising strategy to induce xenotolerance, but may also induce an autoimmune syndrome (AIS). The pathogenesis of this AIS was explored using nude rats as recipients. Thymus grafts consisted of fetal hamster thymic tissue with or without mixing with fetal rat tissue such as thymus, thyroid, salivary gland, and heart. All hamster thymus recipients died of AIS within 2-3 mo. In most recipients of xenothymus mixed with rat tissues such as thymus, thyroid, and salivary gland, but not heart, AIS was prevented, indicating an insufficient presence of rat epithelial cell Ags within the xenothymus. AIS could be transferred to control nude rats by whole splenocytes or by splenocyte subpopulations such as CD3 ؉ , CD3 ؊ , and B lymphocytes, but not by non-T, non-B cells from AIS animals. This transfer could be suppressed by cotransferring either CD4 ؉ or CD8 ؉ lymphocytes from euthymic rats, but not by splenocytes from recipients of syngeneic or xenogeneic thymus mixed with rat tissue, indicating a defective generation of regulatory lymphocytes. As for CD4 ؉ regulatory cells this defect was probably qualitative, because the percentages of CD4 ؉ CD25 ؉ or CD4 ؉ CD45RC low populations were normal after xenothymus transplantation. As for the CD8 ؉ regulatory cells, the defect was quantitative, as CD8 ؉ cell levels always remained low. The latter was related to the nonvascularized nature of thymus grafts. In conclusion, AIS after xenothymus transplantation in nude rats is due to a combination of insufficient intrathymic presence of host-type epithelial cell Ags and a defective generation of regulatory T lymphocytes.
Autoimmune diatheses and T lymphocyte immunoincompetences in BB rats
Metabolism, 1983
EtB rats were found to have autoantibodies to gastric parietal cells, thyroid colloid antigens, smooth muscle, and thymocytes. No autoentibodies reactive with pancreatic islet ceils (cyzoptasmicL th~id epithelial cells, adrenal cortex, testes, or anterior pituitary sections were identified. BB rats with gastric parietal autoantibodies had modest degrees of lymphocytic gas'Critis, but none developed iron or vitamin Btz deficiencies. These results suggest that BB rats have an underlying autoimmune diathesis. In addition, reports of peripheral T lymphopenia in such rats were confirmed, and mmkedly reduced helper T cell and cytotoxic.supprassor T cell subsets were demonstrated. Histological studies also revealed depletions ot the T cell areas of spleen end lymph nodes. Furthermore, BB rats exhibited a profound inability to reject skin grafts across major and minor histocompatibility barriers. This was confirmed by mixed lymphocyte culture studies in vitro. BB-rat ~ymphocytes from either spleen or peripheral blood also showed profoundly reduced responses to T cell mitogens. Although BB-rat {ymphocytes could produce normal levels of {nterleukin-2, they were unable to respond to this T celt growth factor. However, examination of thymuses from BB rats showed largely normal histologies, normal numbers of thvmocyte subsets, and good mitogenic responses to con A, Thus. it appears that BB rats may have a thymic or post thymic defect in T lymphocyte maturation. The re|evance of the immunologic lesion to the etiology of {DO in BB rats remains to be shown.