(1/762) Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection.
A key question in understanding the status of the immune system in HIV-1 infection is whether the adult thymus contributes to reconstitution of peripheral T lymphocytes. We analyzed the thymus in adult patients who died of HIV-1 infection. In addition, we studied the clinical course of HIV-1 infection in three patients thymectomized for myasthenia gravis and determined the effect of antiretroviral therapy on CD4(+) T cells. We found that five of seven patients had thymus tissue at autopsy and that all thymuses identified had inflammatory infiltrates surrounding lymphodepleted thymic epithelium. Two of seven patients also had areas of thymopoiesis; one of these patients had peripheral blood CD4(+) T-cell levels of <50/mm3 for 51 months prior to death. Of three thymectomized patients, one rapidly progressed to AIDS, one progressed to AIDS over seven years (normal progressor), whereas the third remains asymptomatic at least seven years after seroconversion. Both latter patients had rises in peripheral blood CD4(+) T cells after antiretroviral therapy. Most patients who died of complications of HIV-1 infection did not have functional thymus tissue, and when present, thymopoiesis did not prevent prolonged lymphopenia. Thymectomy before HIV-1 infection did not preclude either peripheral CD4(+) T-cell rises or clinical responses after antiretroviral therapy. (+info)
(2/762) Peripheral autoantigen induces regulatory T cells that prevent autoimmunity.
Previous studies have shown that autoimmune thyroiditis can be induced in normal laboratory rats after thymectomy and split dose gamma-irradiation. Development of disease can be prevented by reconstitution of PVG rats shortly after their final irradiation with either peripheral CD4(+)CD45RC- T cells or CD4(+)CD8(-) thymocytes from syngeneic donors. Although the activity of both populations is known to depend on the activities of endogenously produced interleukin 4 and transforming growth factor beta, implying a common mechanism, the issue of antigen specificity of the cells involved has not yet been addressed. In this study, we show that the regulatory T cells that prevent autoimmune thyroiditis are generated in vivo only when the relevant autoantigen is also present. Peripheral CD4(+) T cells, from rats whose thyroids were ablated in utero by treatment with 131I, were unable to prevent disease development upon adoptive transfer into thymectomized and irradiated recipients. This regulatory deficit is specific for thyroid autoimmunity, since CD4(+) T cells from 131I-treated PVG.RT1(u) rats were as effective as those from normal donors at preventing diabetes in thymectomized and irradiated PVG.RT1(u) rats. Significantly, in contrast to the peripheral CD4(+) T cells, CD4(+)CD8(-) thymocytes from 131I-treated PVG donors were still able to prevent thyroiditis upon adoptive transfer. Taken together, these data indicate that it is the peripheral autoantigen itself that stimulates the generation of the appropriate regulatory cells from thymic emigrant precursors. (+info)
(3/762) Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity.
Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates. (+info)
(4/762) Congenital myasthenia gravis: clinical and HLA studies in two brothers.
Two brothers with congenital myasthenia gravis are described. In both, ptosis and ophthalmoplegia responded poorly to oral anticholinesterase therapy and to thymectomy. The brothers had two different HLA haplotypes and neither had the HLA-A1-B8-DW3 haplotypes which are commonly associated with myathenia gravis in adult-onset cases. (+info)
(5/762) The value of thymectomy in myasthenia gravis: a computer-assisted matched study.
In the absence of a prospective randomized study of patients treated conservatively or with thymectomy, a computer-assisted retrospective matches study was devised. Of 563 patients treated for myasthenia gravis without thymoma up to 1965, 104 had thymectomy. With computer assistance, each surgical patient was matched with a medical patient on the basis of age, sex, and severity and duration of disease. On this basis 80 of the 104 surgical patients could be matched satisfactorily. There were 16 males and 64 females in each of the matched surgically treated and medical control groups. A complete remission was experienced by 27 of the 78 patients in the surgical group as compared to 6 of the medical group. Improvement was noted by 26 of 78 surgically treated patients and 13 of 78 receiving medical treatment. Survival for patients having thymectomy. Thirty-four patients in the medical group had died as compared to 11 in the surgical group. Comparison of survival in relation to sex, duration of symptoms, or age (less than 30 or less than 30 years) did not show a significant difference. Until more effective treatment is available for myasthenia gravis, thymectomy deserves consideration for both sexes, and with increased age or long duration of symptoms. (+info)
(6/762) Survival of naive CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu.
The diversity of naive CD4 T cells plays an important role in the adaptive immune response by ensuring the capability of responding to novel pathogens. In the past, it has been generally accepted that naive CD4 T cells are intrinsically long-lived; however, there have been studies suggesting some CD4 T cells are short-lived. In this report, we identify two populations of naive CD4 T cells: a long-lived population as well as a short-lived population. In addition, we identify two factors that contribute to the establishment of long-lived naive CD4 T cells. We confirm earlier findings that MHC class II interaction with the TCR on CD4 T cells is important for survival. Furthermore, we find that MHC class II alleles with the correct restriction element for Ag presentation mediate the peripheral survival of naive CD4 T cells more efficiently than other positively selecting alleles, regardless of the selecting MHC in the thymus. The second component contributing to the survival of naive CD4 T cells is contact with the cytokines IL-4 and IL-7. We find that the physiological levels of IL-4 and IL-7 serve to enhance the MHC class II-mediated survival of naive CD4 T cells in vivo. (+info)
(7/762) Invasive thymoma with long-term survival by extensive reoperation.
The recurrence of invasive thymoma is often observed; however, no accepted treatment of recurrent invasive thymoma has yet been established. We herein report a 41-year-old woman with invasive thymoma and pleural dissemination who demonstrated long-term survival after undergoing 4 operations. Based on our findings, reoperation is thus suggested in patients with intrathoracic recurrence and long-term survival can be expected. (+info)
(8/762) The effect of graft-versus-host disease on T cell production and homeostasis.
The aim of this work was to decipher how graft-versus-host disease (GVHD) affects T cell production and homeostasis. In GVHD+ mice, thymic output was decreased fourfold relative to normal mice, but was sufficient to maintain a T cell repertoire with normal diversity in terms of Vbeta usage. Lymphoid hypoplasia in GVHD+ mice was caused mainly by a lessened expansion of the peripheral postthymic T cell compartment. In 5-bromo-2'-deoxyuridine pulse-chase experiments, resident T cells in the spleen of GVHD+ mice showed a normal turnover rate (proliferation and half-life). When transferred into thymectomized GVHD- secondary hosts, T cells from GVHD+ mice expanded normally. In contrast, normal T cells failed to expand when injected into GVHD+ mice. Thus, the reduced size of the postthymic compartment in GVHD+ mice was not due to an intrinsic lymphocyte defect, but to an extrinsic microenvironment abnormality. We suggest that this extrinsic anomaly is consistent with a reduced number of functional peripheral T cell niches. Therefore, our results show that GVHD-associated T cell hypoplasia is largely caused by a perturbed homeostasis of the peripheral compartment. Furthermore, they suggest that damage to the microenvironment of secondary lymphoid organs may represent an heretofore unrecognized cause of acquired T cell hypoplasia. (+info)