Thymic Size and Lymphocyte Restoration in Patients with Human Immunodeficiency Virus Infection after 48 Weeks of Zidovudine, Lamivudine, and Ritonavir Therapy

Smith, Kimberly Y.; Valdez, Hernán; Landay, Alan; Spritzler, John; Ha, Kessler; Connick, Elizabeth; Kuritzkes, Daniel R.; Gross, Barry H.; Francis, Isaac R.; McCune, Joseph M.; Lederman, Michael M.

doi:10.1086/315169

Cited by 158 publications

(108 citation statements)

References 16 publications

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“…[10] found abundant thymic tissue measured by a CT slice in half of the untreated adult HIV-1 infected patients over 39 years old. This same group observed that the evolution of naïve T-cells during the follow up was associated with larger thymuses at the end of the treatment period [11].…”

Section: Introductionmentioning

confidence: 84%

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Rubio

Martı́nez-Moya

Leal

et al. 2002

Clinical and Experimental Immunology

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SUMMARYAn important thymus role has been suggested in T-cell repopulation after HAART in adult HIV-1 infected patients. Thymus volume increase after treatment has been described in HIV-1 infected children but not in adult patients. The objective of this work was to evaluate the effect of HAART on the thymic volume of adult HIV-1 infected patients and its relation with the T-cell repopulation. Twenty-one adult patients following 24 weeks under HAART were included in the study. All patients underwent a thoracic computed tomography (CT) evaluation for the measurement of thymic volumes at weeks 0, 12 and 24.Baseline thymus volume showed a significant correlation with the patient's age. Thymic volume significantly increased after 24 weeks of HAART. Besides, a significant correlation between changes in the thymus volume and changes in both total and naïve CD4+ cell counts was found. Only patients with increases ≥ 100 CD4+ cell counts after treatment significantly increased the thymic volume.These data show the first evidence of an early change in thymic volume of adult HIV-1 infected patients under HAART. This increase was related to the rise of both total and naïve CD4+ cell counts suggesting a functional role of thymic volume increase.

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Section: Introductionmentioning

confidence: 84%

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Rubio

Martı́nez-Moya

Leal

et al. 2002

Clinical and Experimental Immunology

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“…†Matched unrelated donors were 6/6 HLA matched (18) or 1 locus mismatched (11). Mismatched family donors were haploidentical and T-cell depleted (5), or 1 HLA locus mismatch without T-cell depletion (1).…”

Section: Patientsmentioning

confidence: 99%

“…Thymic size as measured by volumetric computerized tomographic measurements has been correlated with numbers of CD4 ϩ CD45RA ϩ naive T cells. 6,11 The number of phenotypically naive T cells has been shown to correlate with antigen-specific function. 2,3 However, there are concerns about limitations of estimating thymic function on the basis of naive T-cell phenotype alone.…”

Section: Introductionmentioning

confidence: 99%

“…Thymic size as measured by volumetric computerized tomographic measurements has been correlated with numbers of CD4 ϩ CD45RA ϩ naive T cells. 6,11 The number of phenotypically naive T cells has been shown to correlate with antigen-specific function. 2 16,17 A different assay that has been more recently used as a measure of thymopoietic capacity is the frequency of T-cell receptor excision circles (TRECs) among peripheral blood T cells.…”

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confidence: 99%

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Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Weinberg

Blazar

Wagner

et al. 2001

Blood

390

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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“…2,3 Several methods have been used to measure thymopoietic capacity. Thymic size as measured by radiographic imaging 1 and volumetric computed tomography measurements 4,5 have been correlated with numbers of CD4 ϩ CD45RA ϩ naïve T cells, and the number of phenotypically naïve T cells after transplantation has been shown to correlate with antigen-specific function. 6 However, there are concerns about limitations of estimating thymic function based on naïve T-cell phenotype alone.…”

Section: Introductionmentioning

confidence: 99%

Effects of exogenous interleukin-7 on human thymus function

Okamoto

Douek

McFarland

et al. 2002

Blood

125

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Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a ؉ CD3 ؊ CD4 ؉ CD8 ؉ stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3 ؊ cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-␣␤ rearrangement and indicate the potential use of IL-7 for enhancing de novo naïve T-cell generation in immunocompromised patients. ( IntroductionIt has been reported that T-cell numbers are maintained in adults predominantly through the expansion of postthymic, memory T cells, whereas in infants, T cells are predominantly maintained through the production of new naïve T cells by the thymus. 1 However, others and we have recently demonstrated that the adult thymus is still capable of thymopoiesis and can contribute to T-cell reconstitution in adults. 2,3 Several methods have been used to measure thymopoietic capacity. Thymic size as measured by radiographic imaging 1 and volumetric computed tomography measurements 4,5 have been correlated with numbers of CD4 ϩ CD45RA ϩ naïve T cells, and the number of phenotypically naïve T cells after transplantation has been shown to correlate with antigen-specific function. 6 However, there are concerns about limitations of estimating thymic function based on naïve T-cell phenotype alone. T cells expressing a naïve phenotype are not necessarily accurate surrogate markers of thymic function. Following thymic emigration, CD45RA ϩ naïve T cells can have a long quiescent life span, 7 may proliferate in an antigen-independent manner, 8 or may rapidly convert to CD45RO ϩ memory/effector phenotype T cells. 9 Furthermore, naïve T-cell markers may be acquired by memory T cells (especially CD8 ϩ T cells), 9,10 further compounding the difficulty in accurately enumerating naïve T cells. 11,12 To measure thymic function more directly in humans, we recently described an assay that quantifies an episomal DNA by-product of the T-cell receptor (TCR) rearrangement process. 2 These TCR rearrangement excision circles (TRECs) contain the ...

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Thymic Size and Lymphocyte Restoration in Patients with Human Immunodeficiency Virus Infection after 48 Weeks of Zidovudine, Lamivudine, and Ritonavir Therapy

Cited by 158 publications

References 16 publications

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Changes in thymus volume in adult HIV-infected patients under HAART: correlation with the T-cell repopulation

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Effects of exogenous interleukin-7 on human thymus function

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