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Richard D. McFarland

Bio: Richard D. McFarland is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: CD8 & T cell. The author has an hindex of 6, co-authored 6 publications receiving 2197 citations.

Papers
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Journal ArticleDOI
17 Dec 1998-Nature
TL;DR: It is found that, although thymic function declines with age, substantial output is maintained into late adulthood and this results indicate that the adult thymus can contribute to immune reconstitution following HAART.
Abstract: The thymus represents the major site of the production and generation of T cells expressing alphabeta-type T-cell antigen receptors. Age-related involution may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection; this effect has been seen after chemotherapy and bone-marrow transplantation. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells. These cells could arise through expansion of existing naive T cells in the periphery or through thymic production of new naive T cells. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.

1,849 citations

Journal ArticleDOI
TL;DR: It is demonstrated that alphaE integrin (CD103) expression is up-regulated very late in thymic development on a subset of CD8(+)/CD4(-) thymocytes and also defines a distinct subset of naiveCD8(+) T cells in the periphery, which suggest that these cells are a population of RTE and that quantification of their frequency in peripheral blood provides an estimate of the level of ongoing thymopoiesis.
Abstract: The ability to measure human thymic output would be an invaluable tool for the study of the development of the naive T cell repertoire, as well as naive T cell regeneration after intensive cytotoxic chemotherapy or effective antiretroviral therapy of progressive HIV infection. We and others have demonstrated previously that quantification of T cell receptor rearrangement excision circles (TREC) within peripheral T cell populations provides insight into the frequency of recent thymic emigrants (RTE) and, therefore, into thymic function. However, measurement of RTE by this approach is complicated by the fact that TREC levels also are determined by turnover within the naive T cell compartment. Here, we report a phenotypic approach to RTE measurement. We demonstrate that αE integrin (CD103) expression is up-regulated very late in thymic development on a subset of CD8+/CD4− thymocytes and also defines a distinct subset of naive CD8+ T cells in the periphery. The latter subset is differentiated from circulating CD103+ mucosa-associated memory T cells by its naive T cell phenotype (CD45RO−, CD62Lbright, CD27bright, CD11adim, CD95dim) and its high concentration of TREC. Indeed, sorted CD103+ naive CD8+ cells display higher levels of TREC than their CD103− naive counterparts, and these cells demonstrate an age-related decline in frequency that is enhanced significantly by thymectomy. The thymic dependence of this subset and the cells' relatively evanescent presence in the periphery suggest that these cells are a population of RTE and that quantification of their frequency in peripheral blood provides an estimate of the level of ongoing thymopoiesis.

242 citations

Journal ArticleDOI
TL;DR: Investigation of the role of the thymus in T cell reconstitution in human immunodeficiency virus (HIV)-infected children treated with antiretroviral therapy suggests that HIV has an adverse effect upon thymic function in pediatric HIV infection.
Abstract: Studies were undertaken to investigate the role of the thymus in T cell reconstitution in human immunodeficiency virus (HIV)‐infected children treated with antiretroviral therapy. Nine pediatric patients who acquired HIV perinatally were treated with multidrug combinations of antiretroviral agents. Plasma virus load and CD4 + and CD8 + T cell subsets were measured, and thymus function was measured by quantifying T cell receptor rearrangement excision circles in peripheral blood. Patients with virus loads remaining 1400 RNA copies/ mL plasma were classified as virologic nonresponders. Thymus function was initially decreased in all subjects. After antiretrovirus therapy, peripheral CD4 + T cells increased in all subjects. Thymus function was restored in 4 of 5 virologic responders but in only 1 of 4 virologic nonresponders. This suggests that HIV has an adverse effect upon thymic function in pediatric HIV infection. Potent antiretroviral therapy restores thymic function but is affected by the degree to which virus suppression is achieved.

108 citations

Journal ArticleDOI
TL;DR: The findings of erythroid maturation and abundant viral inclusions in these immunocompromised patients is consistent with the hypothesis that failure to produce effective IgG parvovirus neutralizing antibodies may lead to persistent infection through viral tolerance that allows erythyroid development of infected cells past the pronormoblast stage.

28 citations

Journal ArticleDOI
TL;DR: This article used a lentivirus-based gene transfer system to mark CD34 + cells with EGFP and follow their differentiation into CD4 + and CD8 + single positive thymocytes in human thymic organ cultures.

9 citations


Cited by
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Journal ArticleDOI
TL;DR: These Guidelines were developed by the Panel* on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation.
Abstract: SUMMARY The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring including plasma HIV RNA, CD4 cell counts and HIV drug resistance testing. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance due to non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic

4,321 citations

Journal ArticleDOI
TL;DR: NOD-scid IL2Rγnull mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.
Abstract: Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common gamma-chain deficient NOD/LtSz-scid (NOD-scid IL2Rgamma(null)) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2Rgamma(null) mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. Engraftment of NOD-scid IL2Rgamma(null) mice with human HSC generate 6-fold higher percentages of human CD45(+) cells in host bone marrow than with similarly treated NOD-scid mice. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Spleens from engrafted NOD-scid IL2Rgamma(null) mice contain human Ig(+) B cells and lower numbers of human CD3(+) T cells. Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4(+)CD8(+) thymocytes as well human CD4(+)CD8(-) and CD4(-)CD8(+) peripheral blood and splenic T cells. De novo human T cell development in NOD-scid IL2Rgamma(null) mice was validated by 1) high levels of TCR excision circles, 2) complex TCRbeta repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2Rgamma(null) mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.

1,563 citations

Journal ArticleDOI
TL;DR: A long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells is described.
Abstract: Immunological memory is thought to depend on a stem cell–like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+ T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell–like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.

1,526 citations

Journal ArticleDOI
TL;DR: Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency and allow patients to have a normal life.
Abstract: Background X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common γ (γc) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the γc gene can restore the immune system in patients with severe combined immunodeficiency. Methods CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the γc transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer. Results No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro pro...

1,111 citations

Journal ArticleDOI
01 Apr 2003-Blood
TL;DR: It is found that a large proportion of HIV-specific CD8(+) T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture.

950 citations