Effacing of the T Cell Compartment by Cardiac Transplantation in Infancy

Ogle, Brenda M.; West, Lori J.; Driscoll, David J.; Strome, Scott E.; Razonable, Raymund R.; Payá, Carlos V.; Cascalho, Marília; Platt, Jeffrey L.

doi:10.4049/jimmunol.176.3.1962

Cited by 50 publications

(57 citation statements)

References 41 publications

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“…We (15) have found that human subjects who undergo cardiac transplantation in infancy have profound contraction of the TCR repertoire, with diversity of V␤ being as low as 10 4 (compared with 10 6 in age matched controls), but do not suffer a heightened risk of disseminated viral infections or of infections with opportunistic organisms or tumors compared with other transplant recipients. In the course of cardiac transplantation (or nontransplant cardiac surgery) early in life, the thymus is removed and the recipient is treated with Thymoglobulin or anti-CD3 to deplete mature T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although the TCR repertoire contracts profoundly with age (14) and elderly individuals can suffer disseminated viral infections and heightened susceptibility to tumors, most elderly individuals experience neither of these ailments (compared with those who have AIDS). Still more dramatic is the observation that those who undergo cardiac transplantation in infancy and have a profound contraction of the TCR repertoire owing to "total" thymectomy and mature T cell depletion suffer no excess of opportunistic infections or tumors (15).…”

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confidence: 99%

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Fitness of Cell-Mediated Immunity Independent of Repertoire Diversity

AbuAttieh¹,

Rebrovich²,

Wettstein³

et al. 2007

The Journal of Immunology

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Fitness of cell-mediated immunity is thought to depend on TCR diversity; however, this concept has not been tested formally. We tested the concept using JH−/− mice that lack B cells and have TCR Vβ diversity <1% that of wild-type mice and quasimonoclonal (QM) mice with oligoclonal B cells and TCR Vβ diversity 7% that of wild-type mice. Despite having a TCR repertoire contracted >99% and defective lymphoid organogenesis, JH−/− mice rejected H-Y-incompatible skin grafts as rapidly as wild-type mice. JH−/− mice exhibited T cell priming by peptide and delayed-type hypersensitivity, although these responses were less than normal owing either to TCR repertoire contraction or defective lymphoid organogenesis. QM mice with TCR diversity contracted >90%, and normal lymphoid organs rejected H-Y incompatible skin grafts as rapidly as wild type mice and exhibited normal T cell priming and normal delayed-type hypersensitivity reactions. QM mice also resisted Pneumocystis murina like wild-type mice. Thus, cell-mediated immunity can function normally despite contractions of TCR diversity >90% and possibly >99%.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Fitness of Cell-Mediated Immunity Independent of Repertoire Diversity

AbuAttieh¹,

Rebrovich²,

Wettstein³

et al. 2007

The Journal of Immunology

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“…Previous short-term surveys showed that thymectomized children have reduced CD4 + T cell and TCR excision circle numbers compared with age-matched controls (6)(7)(8)(9)(10). More recently, reduction of naive CD4 + T cell numbers and production in thymectomized patients was shown to correlate with chronological age and time since thymectomy (11).…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of PBMC samples from YATECs, taken an average of 2 decades after thymectomy, revealed clear alterations in the CD4 + T cell compartment (as expected from previous studies on CHD patients; ref. [6][7][8][9][10][11] as well as in the CD8 + T cell compartment. We found decreased CD4 + and CD8 + T cell counts in YATECs compared with age-matched controls, and even compared with middle-aged adult controls (Figure 2A).…”

Section: Introductionmentioning

confidence: 99%

Evidence of premature immune aging in patients thymectomized during early childhood

Sauce¹,

Larsen²,

et al. 2009

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While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4 + and CD8 + T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

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“…32 We also showed that under physiological conditions, diversity of T cells in humans correlates directly with the level of thymic function and correlates with the level of TREC in blood. 33,34 We focused our analyses on the human a chain of the TCR because porcine b chain of the TCR is quite homologous with human. A primer specific for the human a chain was used to extract TCRVa-specific RNA from PBMC, which was biotinylated and applied to a gene chip.…”

Section: Diversity Of Human T Cells In Chimeric Swinementioning

confidence: 99%

Toward Development and Production of Human T Cells in Swine for Potential Use in Adoptive T Cell Immunotherapy

Ogle

Knudsen

Nishitai

et al. 2009

Tissue Engineering Part A

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Immunotherapy and vaccination for cancer or infection are generally approached by administration of antigen or stimulation of antigen-presenting cells or both. These measures may fail if the treated individual lacks T cells specific for the immunogen(s). We tested another strategy-the generation of new T cells from hematopoietic stem cells that might be used for adoptive immunotherapy. To test this concept, we introduced T cell-depleted human bone marrow cells into fetal swine and tested the swine for human T cells at various times after birth. Human T cells were detected in the thymus and blood of the treated swine. These cells were generated de novo as they contained human T cell receptor excision circles not present in the T cell-depleted bone marrow. The human T cells were highly diverse and included novel specificities capable of responding to antigen presented by human antigen-presenting cells. Our findings constitute a first step in a new promising approach to immunotherapy in which tumor-or virus-specific T cell clones lacking in an individual might be generated in a surrogate host from hematopoietic stem cells of the individual to be treated.

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Effacing of the T Cell Compartment by Cardiac Transplantation in Infancy

Cited by 50 publications

References 41 publications

Fitness of Cell-Mediated Immunity Independent of Repertoire Diversity

Fitness of Cell-Mediated Immunity Independent of Repertoire Diversity

Evidence of premature immune aging in patients thymectomized during early childhood

Toward Development and Production of Human T Cells in Swine for Potential Use in Adoptive T Cell Immunotherapy

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