Reduction of CD45RA Isoform Expression and Decrease in CD4 and CD8 Receptor Density in Lymphocytes of Patients with Primary Biliary Cirrhosis

Musialik, Joanna; Michałkiewicz, Jacek; Petelenz, Michał; Mazurek, Urszula; Mazur, W.; Madaliński, K; Gonciarz, Z

doi:10.1080/00365520310000843

Cited by 6 publications

(6 citation statements)

References 24 publications

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“…NKT cells, normally abundant in the liver, are not increased in the liver in PBC, 29 and in IL-2R␣ Ϫ/Ϫ mice these were actually decreased in number and proportion in both liver and spleen. In PBC most CD4 ϩ T cells are of the CD45RO high memory phenotype 30,31 and, similarly, in the mice, there was a significant increase in CD44 ϩ memory cells among both CD4 ϩ and CD8 ϩ T cells populations consistent with the chronic autoimmune nature of the disease in both humans and the mouse model.…”

Section: Discussionmentioning

confidence: 57%

IL-2 receptor α−/− mice and the development of primary biliary cirrhosis

et al. 2006

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Recently, we identified a child born with a genetic deficiency of IL-2 receptor ␣ (IL-2R␣, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC). In addition, there has been suggestive evidence in both patients with PBC and their first-degree relatives that a deficiency of regulatory T cells (Tregs) is an integral component for susceptibility to PBC. Based on these observations, we generated IL-2R␣/CD25 deficient (IL-2R␣ ؊/؊ ) mice and wildtype littermate controls and followed them longitudinally for the natural history of liver immunopathology and appearance of antimitochondrial antibodies (AMAs). The analyses included immunohistochemical staining of liver and portal tract infiltrates as well as FACS profiles of lymphoid subpopulations in liver and spleen. In addition, serum cytokine profiles were quantitated. Importantly, IL-2R␣ ؊/؊ , but not littermate controls, develop portal inflammation and biliary ductular damage similar to human patients with PBC. CD4 ؉ and CD8 ؉ T cells predominate among portal cell infiltrates and sera reflect a Th1 cytokine bias with increased levels of IFN-␥, TNF-␣, IL-2 and IL-12p40. Of importance is the finding that the IL-2R␣ ؊/؊ mice not only develop significantly increased serum levels of IgG and IgA, but they also develop AMAs with specificity for PDC-E2, which maps to the inner lipoyl domain of the autoantigen, all characteristics which are hallmarks of human PBC. In conclusion, the IL-2R␣ ؊/؊ mice should facilitate studies of the early events in PBC and especially the tantalizing connection between Treg deficiency and autoimmunity specifically directed to mitochondrially located PDC-E2 and subsequent biliary ductular cell damage. (HEPATOLOGY 2006;44:1240-1249.) P rimary biliary cirrhosis (PBC) is a chronic autoimmune liver disease primarily affecting smaller intrahepatic bile ducts and characterized by autoantibodies to the mitochondrially located E2 subunits of pyruvate dehydrogenase and related enzymes (PDC-E2), traditionally known as antimitochondrial antibodies (AMA). 1 A better understanding of the initial pathologic events will lead to better understanding for this eventually morbid and often fatal human disease. In particular, the early immunologic events in PBC have remained obscure, partly because of the long asymptomatic period. Clearly animal models of human PBC would greatly facilitate studies of the etiology of this disease and specially facilitate the identification of the early events that lead to this disease. Two murine models have recently been described that provide data which suggest that indeed this goal may be achieved. The first is the presence of AMA and severe biliary disease in a congenic strain of NOD mice, coined NOD.c3c4. 2,3 The second model is the appearance of autoimmune cholangitis and AMAs in TGF-␤ receptor II dominant-negative mice. 4 We have also seen a PBC-like disease in a child with homozygous IL-2R␣ (CD25) deficiency. 5 This latter finding is of interest since our laboratory has previously documente...

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Section: Discussionmentioning

confidence: 57%

IL-2 receptor α−/− mice and the development of primary biliary cirrhosis

et al. 2006

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“…NKT cells, normally abundant in the liver, are not increased in the liver in PBC,29 and in IL‐2Rα −/− mice these were actually decreased in number and proportion in both liver and spleen. In PBC most CD4 + T cells are of the CD45RO high memory phenotype30, 31 and, similarly, in the mice, there was a significant increase in CD44 + memory cells among both CD4 + and CD8 + T cells populations consistent with the chronic autoimmune nature of the disease in both humans and the mouse model.…”

Section: Discussionmentioning

confidence: 60%

Incidence of chemotherapy‐induced, long‐term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane

Fornier

Modi

Panageas

et al. 2005

Cancer

165

100

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BACKGROUNDTwenty‐five percent of all women with breast carcinoma are premenopausal and are at risk for chemotherapy‐induced menopause with long‐term side effects. Although there is considerable documentation of the rates of chemotherapy‐induced amenorrhea with classic adjuvant regimens, there are inadequate data that address the impact of taxanes on menstrual function in this setting. The objective of this analysis was to determine the incidence of long‐term amenorrhea (≥ 12 mos) in women with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane‐based chemotherapy, with or without subsequent tamoxifen.METHODSThe authors identified 235 premenopausal women with breast carcinoma age 40 years or younger who were treated with adjuvant anthracycline and taxane‐based chemotherapy at Memorial Sloan‐Kettering Cancer Center from January 1997 to June 2003.RESULTSOne hundred sixty‐six patients met all eligibility criteria and had sufficient follow‐up for evaluation. The median age of patients at diagnosis was 36 years (range, 27–40 yrs). All patients had regular pretreatment menses, 25 patients (15%) developed long‐term amenorrhea, and 141 patients (85%) resumed menstruation. Eighty‐two patients (49%) also received tamoxifen: The incidence of amenorrhea among them was 17%. There was a statistically significant association between age and the development of amenorrhea, with older women at higher risk. (P < 0.01)CONCLUSIONSThe sequential addition of a taxane to standard adjuvant anthracycline‐based chemotherapy did not appear to produce a high rate of chemotherapy‐related amenorrhea compared with historic controls. To increase the information available to assist young patients who are considering adjuvant therapy, prospective studies should incorporate menstrual function ascertainment by patient‐reported history and assays of ovarian function. Cancer 2005. © 2005 American Cancer Society.

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“…11 We noted a small but significant decrease in expression of CD38 on CD4 + lymphocytes after thawing and resting, and a consistent but statistically insignificant increase in CD69 in total, CD4 and CD8 lymphocytes. Elevated expression of CD69 has been noted in the peripheral blood of patients with some cirrhotic liver diseases 34 and decreased CD38 expression 35 observed in patients with transfusional iron overload. However, the changes seen were modest, were not accompanied by an increase in cell size by forward/side scatter which would suggest proliferation 7,27,33 and we do not observe spontaneous proliferation in cryopreserved cells.…”

Section: Selective Effects Of Cryopreservation On Lymphocyte Subsetsmentioning

confidence: 99%

Functional Consequences of Human Lymphocyte Cryopreservation

Faint

Tuncer

Garg

et al. 2011

Journal of Immunotherapy

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In order to understand human inflammatory diseases and to develop and assess new therapeutic strategies targeting leukocyte recruitment to tissue, it is necessary to study human lymphocyte interactions with endothelium. It is often not practical to carry out assays on fresh human samples and therefore cells may be cryopreserved and batched for later study. Furthermore, many forms of adoptive cell therapy use cryopreserved cells that are required to migrate to tissue after infusion in vivo. The consequences of cryopreservation on the adhesion and migration of leukocytes is not known leading us to study the effects of cryopreservation on lymphocyte phenotype, migration, and adhesion. Cryopreservation and subsequent thawing did not alter the proportion of retrieved T cell subsets. Overall levels of expression of β1 or β2 integrins were unaffected but marked changes were observed in other relevant receptors. Expression of CD69, a transmembrane protein that plays a critical role in lymphocyte egress from tissues and the chemokine receptor CXCR4, increased on thawed populations and levels of CD62L and CXCR3 were reduced on thawed cells but restored if cells were allowed to recover after thawing. These changes were associated with modulation of the ability of lymphocytes to migrate across cytokine-stimulated monolayers of endothelium toward recombinant CXCL11 and CXCL12. Thus cryopreservation and thawing of lymphocytes induces changes in their adhesive phenotype and modulates their ability to migrate across endothelial monolayers. These findings have implications for in vitro experimentation and for cell therapy in which cryopreserved cells are expected to migrate when reinfused into patients.

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Reduction of CD45RA Isoform Expression and Decrease in CD4 and CD8 Receptor Density in Lymphocytes of Patients with Primary Biliary Cirrhosis

Abstract: It is concluded that the reduction in number of 'suppressor-inducer-like 'naive' CD4+ T-cell subsets in association with the decrease in fluorescence intensity for CD4 and CD8 may significantly contribute to the mechanisms that could account for a development of PBC.

Cited by 6 publications

References 24 publications

IL-2 receptor α−/− mice and the development of primary biliary cirrhosis

IL-2 receptor α−/− mice and the development of primary biliary cirrhosis

Incidence of chemotherapy‐induced, long‐term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane

Functional Consequences of Human Lymphocyte Cryopreservation

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