T Cell Subsets in the Thymus of Graft-Versus-Host Immunosuppressed Mice: Sensitivity of the L3t4+lyt-2− Subset to Cortisone

Kornbluth, Murray; You-Ten, Eric; Desbarats, Julie; Gamache, Stéphanie; Xenocostas, Anargyros; Lapp, Wayne S.

doi:10.1097/00007890-199101000-00044

Cited by 14 publications

(6 citation statements)

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“…Rodent studies have indicated that the administration of cortisone to animals undergoing a graft-versus-host response results in a reduction of mature thymocytes, particularly those bearing the CD4 antigen. 30 Although exogenous glucocorticoids are known to cause thymocyte apoptosis in vitro, little is known of their effect on thymic output in humans. 56 Thus, the observed continued increase in TREC levels in spite of continued glucocorticoids was unexpected.…”

Section: Discussionmentioning

confidence: 99%

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Weinberg

Blazar

Wagner

et al. 2001

Blood

389

291

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Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA ؉ naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graftversus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4 ؉ and CD8 ؉ cells from a crosssection of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to posttransplant thymopoietic capacity. IntroductionFollowing hematopoietic stem cell transplant (HSCT), there is a prolonged period of profound immune deficiency, which includes defects in thymopoiesis. 1 This immune deficiency contributes to the high incidence of opportunistic infection, which continues for years after HSCT. 2,3 The etiology of the immune defect is multifactorial. Thymopoietic defects resulting in decreased ability to generate new T cells after HSCT are important since complete immune reconstitution ultimately depends on the generation of new T cells from hematopoietic stem cell (HSCs), just as long-term myeloid and erythroid reconstitution depends on HSC engraftment. Transfer of committed progenitors or mature donor-derived T cells may permit short-term immune function. Analyses of patients after HSCT have demonstrated that the presence of immune function at 1 year or later was correlated with the number of CD4 ϩ CD45RA ϩ naive T cells, suggesting that immune function at later time points is dependent on the ability to generate new T cells. 4,5 The factors that inhibit thymic function may include age, graft-versus-host disease (GVHD), and direct thymic damage from chemoradiotherapy. In multiple studies of normal individuals, recipients of high-dose chemotherapy, HSCT recipients, and patients infected with human immunodeficiency virus, age has been inversely correl...

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Section: Discussionmentioning

confidence: 99%

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Weinberg

Blazar

Wagner

et al. 2001

Blood

389

291

View full text Add to dashboard Cite

show abstract

“…BM Reconstitution Experiments. BM transplantation were performed in 129/sv inbred mice to avoid the complications of allograft rejection and graft-versus-host disease (32,34). Inbred mice were generated by mating 129/sv female mice with chimeric male mice which gave rise to germ line offsprings.…”

Section: Methodsmentioning

confidence: 99%

Impaired Bone Marrow Microenvironment and Immune Function in T Cell Protein Tyrosine Phosphatase–deficient Mice

You-Ten

Muise

Itié

et al. 1997

The Journal of Experimental Medicine

Self Cite

333

306

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The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP–deficient mutant mice. The three genotypes (+/+, +/−, −/−) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3–5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP −/− animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

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“…GVHR Induction. GVHRs were induced as described previously (4). Briefly, pooled parental spleen and lymph nodes were made into single-cell suspensions and injected intravenously into unirradiated F1 hybrid recipients (28).…”

Section: Methodsmentioning

confidence: 99%

“…Survivors of the acute reaction develop chronic GVHR, a multisystem disease characterized by autoimmune features and persistent immunosuppression (1)(2)(3). These manifestations of chronic GVHR represent T cell functional abnormalities possibly resulting from defective education within the GVHR-dysplatic thymus (4,5). Indeed, the thymus sustains severe histopathological damage during acute GVHR, including injury to medullary epithelial ceils, effacement of the corticomedullary junction, progressive disappearance of I Abbreviation used in this paper: GVHR, graft-vs.-host reaction.…”

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confidence: 99%

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Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions.

Desbarats

Lapp

1993

The Journal of Experimental Medicine

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Sumnlal~The graft-vs.-host reaction (GVHR) results in damage to the epithelial and lymphoid compartments of the thymus and thus in abnormal maturation and function of thymocytes in mice undergoing GVHR. In this report, the effects of GVHR on thymic T cell receptor (TCR) expression and usage have been investigated. GVHK was induced in unirradiated F1 hybrid mice by the intravenous transfer of parental lymphoid cells. Expression of the CD3/TCR complex on thymocyte subsets defined by CD4 and CD8 was studied by three-color flow cytometry. The level of CD3/TCK was decreased on CD4+CD8 -, but not CD4-CD8 § mature thymocytes. The lack of upregulation of CD3/TCR on CD4 single-positive thymocytes, but not on their CD8 + counterparts, suggested an abnormality of class II major histocompatibility complex (MHC) expression in the thymuses of mice undergoing GVHK. Immunofluorescence staining of thymic frozen sections revealed that MHC class II expression was dramatically decreased in GVH-reactive mice. GVHK-induced changes in positive and negative selection were evaluated by determining the incidence of specific VB TCK segment usage in the thymus. In normal mice, thymocyte usage of any given V3 segment was highly consistent between individuals of the same strain and age; however, a marked divergence in the incidence of TCK V36 hi and VB8 hi cells between GVH-reactive littermate mice was observed, suggesting that thymic positive selection had become disregulated in these animals. Furthermore, negative selection was defective; the incidence of phenotypically self-reactive VB6 hi T cells was significantly greater in the thymuses of GVHreactive mice bearing the endogenous superantigen Mls-P than in untreated controls. Thus, mice undergoing GVHK showed defective TCK upregulation on CD4+CD8 -thymocytes and changes in TCK usage reflecting aberrant thymic selection, in conjunction with decreased expression of MHC class II. Most abnormalities of TCR expression and usage on CD4 + thymocytes observed in GVH-reactive mice were analogous to those of class II knockout mice.

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T Cell Subsets in the Thymus of Graft-Versus-Host Immunosuppressed Mice: Sensitivity of the L3t4+lyt-2− Subset to Cortisone

Cited by 14 publications

References 0 publications

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Impaired Bone Marrow Microenvironment and Immune Function in T Cell Protein Tyrosine Phosphatase–deficient Mice

Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions.

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