Role of the thymus in murine lupus and cellular transfer of the disease

Theofilopoulos, Argyrios N.

doi:10.1002/art.1780250703

Cited by 31 publications

(12 citation statements)

References 27 publications

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“…It is well known that autoimmune-prone mice show high levels of CICs and anti-dsDNA antibodies with age (18,19). We measured antibodies to dsDNA and CICs as previously described.…”

Section: Resultsmentioning

confidence: 99%

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

Ikehara¹,

Good²,

Nakamura³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

225

136

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Transplantation of normal bone marrow from C3H/HeN nu/nu (H-2k) mice into young MRL/MPlpr/lpr (MRL/I; H-2k) mice (<1.5 mo) prevented the development of autoimmune diseases and characteristic thymic abnormalities in the recipient mice. When female MRL/1 (>2 mo) or male BXSB (H-2b) mice (9 mo) with autoimmune diseases and lymphadenopathy were lethally irradiated and then reconstituted with allogeneic bone marrow cells from young BALB/c nu/nu (H-2d) mice (<2 mo), the recipients survived for more than 3 mo after the bone marrow transplantation and showed no graft-versus-host reaction. Histopathological study revealed that lymphadenopathy disappeared and that all evidence of autoimmune disease either was prevented from developing or was completely corrected even after its development in such mice. All abnormal T-cell functions were restored to normal. The newly developed T cells were found to be tolerant of both bone marrow donor-type (BALB/c) and host-type (MRL/I or BXSB) major histocompatibility complex (MHC) determinants. Therefore, T-cell dysfunction in autoimmuneprone mice can be associated with both the involutionary changes that occur in the thymus of the autoimmune-prone mice and also to abnormalities that reside in the stem cells.However, normal stem cells from BALB/c nu/nu donors can differentiate into normal functional T cells even in mice whose thymus had undergone considerable involution, as in the case of BXSB or MRL/I mice in the present studies. These findings suggest that marrow transplantation may be a strategy ultimately to be considered as an approach to treatment of lifethreatening autoimmune diseases in humans. T-cell dysfunction in autoimmune-prone mice previously attributed to involutionary changes that occur in the thymus of these mice may instead be attributed to abnormalities that basically reside in the stem cells of the autoimmune-prone mice.The availability of several murine strains that develop systemic lupus erythematosus-like disease has prompted efforts to gain better understanding of the fundamental nature of autoimmune diseases through extensive studies of the immunological abnormalities of these mice. MRL/MP-lpr/lpr (MRL/l) and BXSB mice as well as NZB mice and NZB x NZW F1 hybrids spontaneously develop autoimmune diseases characterized by anti-double-stranded (ds) DNA antibodies, immune-complex glomerulonephritis, and death from renal failure (1). Abnormalities have been found in or attributed to T cells, thymic epithelium, B cells, and/or macrophages in these mice (2-8). Recently, several groups have shown that the proneness to develop autoimmune diseases actually resides in defects at the lymphoid stem-cell level and that defects of function are not directly attributable to environmental factors such as hormones or viruses (9-11).Therefore, we examined whether or not transfer of normal stem cells into autoimmune-prone mice can be used to both prevent and treat autoimmune diseases.In the present study, we show that allogeneic bone marrow transplantation from donors carry...

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“…It is well known that autoimmune-prone mice show high levels of CICs and anti-dsDNA antibodies with age (18,19). We measured antibodies to dsDNA and CICs as previously described.…”

Section: Resultsmentioning

confidence: 99%

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

Ikehara¹,

Good²,

Nakamura³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

225

136

View full text Add to dashboard Cite

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“…autoimmunity is associated with the emergence of a lymphoid cell population of unusual phenotype (Lyl+-, dThy-l+, L3T4-) (3). Abnormal immunoregulation by T cells is clearly implicated in the pathogenesis of the disease since depletion of T cells by monoclonal anti-T cell antibody (4), thymectomy (5), allogeneic bone marrow transplantation (6), or treatment with cyclosporin (7) can prevent or ameliorate the systemic autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.

Passwell¹,

Schreiner²,

Nonaka³

et al. 1988

J. Clin. Invest.

150

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Systemic lupus erythematosus (SLE) is associated with the presence of complement proteins and immune complexes in affected organs. Since complement proteins are synthesized in hepatic and extrahepatic sites, we studied a murine model of SLE to ascertain the relative importance of local and humoral (liver) synthesis of complement. C3, C4, and C2 mRNA increase in kidney coincident with the development of nephritis in the MRL lpr/lpr mouse, a strain that spontaneously develops SLE. Two factor B messenger RNA transcripts are expressed in kidney and intestine; SLE nephritis is associated with decrease in the long factor B mKNA and increase in the short form. Increased local synthesis of C3 and I1 protein and a concomitant glomerular and renal interstitial macrophage infiltrate paralleled the increase in mRNA content in the (lpr/ lpr) mice. In addition to kidney, an increase in C3, C4, C2 and factor B mRNA was noted in the lung, heart and intestine and to a lesser extent in liver of (Ipr/lpr) in comparison to the MRL (+/+) animals.These results suggest that in SLE local expression of complement genes plays a role in the pathogenesis of chronic glomerulonephritis and in the autoimmune arteritis of other organs.

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“…Transplantation of bone marrow cells from mice resistant to autoimmunity or from mice susceptible to autoimmunity provides an opportunity to elucidate the role of donor genes and/or thymic environment on expression of immunologic abnormalities and susceptibility to disease in mice of these strains (2)(3)(4)(5)(6)(7)(8)(9). Bone marrow transplants matched at the major histocompatibility complex (MHC) from resistant donors to susceptible recipients correct autoimmune disease and many autoimmune abnormalities expressed early in life in the autoimmune-prone mice (2,3,5,(7)(8)(9). However, no one has analyzed the potential of MHC mismatched marrow transplants in these model systems.…”

mentioning

confidence: 99%

Marrow transplantation from tolerant donors to treat and prevent autoimmune diseases in BXSB mice.

Himeno

Good²

1988

Proc. Natl. Acad. Sci. U.S.A.

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Role of the thymus in murine lupus and cellular transfer of the disease

Cited by 31 publications

References 27 publications

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.

Marrow transplantation from tolerant donors to treat and prevent autoimmune diseases in BXSB mice.

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