Fumito Akasu

Impaired generation of high-affinity interleukin-2 receptors in the autologous mixed lymphocyte reaction in rheumatoid arthritis.

We examined the expression of high-affinity interleukin (IL)-2 receptors (IL-2R) as well as Tac and HLA-DR antigens on peripheral blood (PB) T cells from 11 rheumatoid arthritis (RA) patients and 8 healthy controls induced in the autologous mixed lymphocyte reaction (AMLR). The proportion of HLA-DR- and Tac-bearing T cells and expression of these activation antigens were higher in patients relative to controls (P less than 0.01) in freshly isolated unstimulated PB mononuclear cells. AMLR stimulation of RA T cells failed to induce an increase in the proportion of HLA-DR and Tac-bearing T cells which was observed in health controls. After AMLR stimulation the number of high-affinity IL-2R were significantly lower in RA patients compared with controls (P less than 0.01). The number of high-affinity IL-2R on patient T cells correlated strongly with AMLR reactivity as measured by [3H]thymidine incorporation (r = 0.821, P = 0.002). The results suggest that the AMLR defect in RA may result from impaired generation of high-affinity IL-2R.

An Autoimmune Mrl/Mp-Ipr/Ipr Mouse-Derived Monoclonal Igg Antibody Stimulates Cytokine Production in Bone Marrow-Derived Cell Line by Cross-Linking of a Cell Surface Antigen and Fc Receptor

An IgG1 mAb 1G10 derived from an autoimmune MRL/Mp-Ipr/Ipr (MRL/Ipr) mouse has previously been shown to induce IL-3, TNF-alpha and IL-6 production, and autocrine growth in an IL-3-dependent myeloid cell line, FDC-P2/185-4. In the present study, we have attempted to further define the molecular mechanism responsible for the 1G10-induced activation of FDC-P2/185-4 cells. We have shown that 1G10 lacked anti-IgG1 rheumatoid factor activity, failing to generate self-associated immune complexes. Since 1G10 stimulated cells in an Fc gamma R-dependent manner, it seems likely that cross-linking of a cell surface antigen and Fc gamma R by 1G10 antibody is responsible for the stimulation of FDC-P2/185-4 cells. Among several mAb specific to surface antigens expressed on FDC-P2/185-4 cells (MHC class I, LFA-1, and Fc gamma R), only a mAb specific to the alpha chain of LFA-1 alpha was able to induce the IL-3 and Fc gamma R-dependent proliferation of FDC-P2/185-4 cells, similar to that induced by 1G10. Immunoprecipitation analysis revealed that 1G10 recognized a polypeptide with a molecular mass of 140 kilodaltons (p140), which differed from Fc gamma R and from LFA-1 alpha chain. These results suggest that cross-linking of not general but particular cell surface antigens and Fc gamma R stimulates FDC-P2/185-4 cells to produce cytokines resulting in their proliferation.

Thyroid lymphomas in human thyroid tissue with autoimmune thyroid disease xenografted in severe combined immunodeficient mice

Malignant lymphoma of the thyroid (MLT) frequently arises in patients with a background of Hashimoto’s thyroiditis (HT); however, the mechanisms underlying this chain of events are unknown, and there has been no experimental model. Recently, the development of malignant lymphoma has been reported to occur in peripheral blood lymphocytes engrafted into severe combined immunodeficient (SCID) mice. We xenografted human thyroid tissue from patients with HT or Graves disease (GD) into SCID mice to determine the frequency and nature of MLT in these grafts. Human thyroid tissues ( 12 HT, 1 GD, and 15 from normal [paranodular] tissue) were xenografted into 72 mice (43 mice with HT or GD tissue) within 2 hours after human surgery. Human peripheral blood mononuclear cells (PBMC; 4 autologous HT, I allogeneic HT, and 1 allogeneic GD) were injected intraperitoneally into 6 of the latter 43 mice. In addition, 16 additional SCID mice received normal PBMC injections (alone). The mice were killed 6 to 20 weeks after xenografting. In 4 of 33 SCID mice bearing HT thyroid grafts (without addition of PBMC), MLT developed in the HT graft between 8 and 16 weeks after xenografting. In addition, one spleen of a mouse xenografted with GD tissue alone developed a human malignant lymphoma, although the xenografted thyroid in that mouse did not manifest lymphoma. One additional mouse xenografted with HT thyroid tissue and allogeneic HT PBMC developed malignant lymphoma of both the xenografted thyroid and the mouse spleen. In this mouse, the clonality of these lesions in the two organs was different: the thyroid showed restricted expression of immunoglobulin A (IgA) kappa, whereas the spleen exhibited lambda light chain restriction. One human MLT was removed from a SCID mouse, and equal halves were rexenografted into a nude mouse and another SCID mouse. Thyroid antibodies and IgG levels increased in the second SCID mouse, and the MLT survived; in the nude mouse, however, thyroid antibodies and IgG gradually disappeared, and the MLT regressed, virtually to normal. No MLTs were found in the normal human thyroid xenografts. In SCID mice receiving normal PBMC alone, lymphomas tended to develop when more than 35 x 106 cells were engrafted (a number similar to that of the lymphocytes in the HT xenografts); thus, the MLTs may reflect merely the numbers (and perhaps density) of human lymphocytes present in the xenografts. It is possible that committment of many of the HT-infiltrating lymphocytes to the thyroid might add an additional factor. However, whether this model will prove useful to study the possible transition of HT to MLT remains problematic.