Accelerating immune reconstitution after hematopoietic stem cell transplantation

Tzannou, Ifigeneia; Leen, Ann M.

doi:10.1038/cti.2014.2

Cited by 10 publications

(8 citation statements)

References 94 publications

(140 reference statements)

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“…Although engraftment occurs within a few weeks and total blood populations N p and N d (and often immune function) re-establish themselves within a few months after successful HSC transplant [ 43 , 44 ], it is still surprising that the clone size distribution is relatively static within each animal (see Additional file 1 for other animals). Given the observed stationarity, we will use the steady-state results of our mathematical model (explicitly derived in Additional file 1 ) for fitting data from each animal.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques

et al. 2015

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BackgroundHow a potentially diverse population of hematopoietic stem cells (HSCs) differentiates and proliferates to supply more than 1011 mature blood cells every day in humans remains a key biological question. We investigated this process by quantitatively analyzing the clonal structure of peripheral blood that is generated by a population of transplanted lentivirus-marked HSCs in myeloablated rhesus macaques. Each transplanted HSC generates a clonal lineage of cells in the peripheral blood that is then detected and quantified through deep sequencing of the viral vector integration sites (VIS) common within each lineage. This approach allowed us to observe, over a period of 4-12 years, hundreds of distinct clonal lineages.ResultsWhile the distinct clone sizes varied by three orders of magnitude, we found that collectively, they form a steady-state clone size-distribution with a distinctive shape. Steady-state solutions of our model show that the predicted clone size-distribution is sensitive to only two combinations of parameters. By fitting the measured clone size-distributions to our mechanistic model, we estimate both the effective HSC differentiation rate and the number of active HSCs.ConclusionsOur concise mathematical model shows how slow HSC differentiation followed by fast progenitor growth can be responsible for the observed broad clone size-distribution. Although all cells are assumed to be statistically identical, analogous to a neutral theory for the different clone lineages, our mathematical approach captures the intrinsic variability in the times to HSC differentiation after transplantation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0191-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques

et al. 2015

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“…T‐cell reactivity is directed towards a wide range of CMV antigens, and natural killer cells typically increase in response to viral replication 13 , 14 . Adoptive transfer of CMV‐specific T‐cell lines demonstrates promising results in hematopoietic stem cell transplantation (HSCT) recipients 15 , 16 . However, generation of specific T‐cell lines ex vivo and their function in vivo is more complicated in SOT recipients and success has not been achieved previously—a single case report describes generation of CMV‐specific T‐cell lines from a patient with GRCMV disease, however the patient did not survive long term.…”

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confidence: 99%

“…13,14 Adoptive transfer of CMV-specific T-cell lines demonstrates promising results in hematopoietic stem cell transplantation (HSCT) recipients. 15,16 However, generation of specific T-cell lines ex vivo and their function in vivo is more complicated in SOT recipients and success has not been achieved previously-a single case report describes generation of CMV-specific T-cell lines from a patient with GRCMV disease, however the patient did not survive long term. 17 In HSCT, peripheral blood mononuclear cells (PBMCs) taken as starting material for CMV-specific T-cell generation are derived from healthy donors.…”

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confidence: 99%

Adoptive T‐cell immunotherapy for ganciclovir‐resistant CMV disease after lung transplantation

et al. 2015

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Infections with cytomegalovirus (CMV) can induce severe complications after solid organ transplantation (SOT). The prognosis for ganciclovir-resistant CMV infection and disease is particularly poor. Whereas adoptive transfer of CMV-specific T cells has emerged as a powerful tool in hematopoietic stem cell transplant patients, its translation into the SOT setting remains a significant challenge as underlying immunosuppression inhibits the virus-specific T-cell response in vivo. Here, we demonstrate successful expansion and adoptive transfer of autologous CMV-specific T cells from a seronegative recipient of a seropositive lung allograft with ganciclovir-resistant CMV disease, resulting in the long-term reconstitution of protective anti-viral immunity, CMV infection, disease-free survival and no allograft rejection.

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“…Although engraftment occurs within a few weeks and total blood populations N p and N d (and often immune function) re-establish themselves within a few months after successful HSC transplant [43,44], it is still surprising that the clone sizedistribution is relatively static within each animal (see Additional File for other animals). Given the observed stationarity, we will use the steady-state results of our mathematical model (explicitly derived in the Additional File) for fitting data from each animal.…”

Section: Results and Analysismentioning

confidence: 99%

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaque

Goyal

Kim

Chen

et al. 2015

Preprint

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How a potentially diverse population of hematopoietic stem cells (HSCs) differentiates and proliferates to supply more than 10 11 mature blood cells every day in humans remains a key biological question. We investigated this process by quantitatively analyzing the clonal structure of peripheral blood that is generated by a population of transplanted lentivirus-marked HSCs in myeloablated rhesus macaques. Each transplanted HSC generates a clonal lineage of cells in the peripheral blood that is then detected and quantified through deep sequencing of the viral vector integration sites (VIS) common within each lineage. This approach allowed us to observe, over a period of 4-12 years, hundreds of distinct clonal lineages. Surprisingly, while the distinct clone sizes varied by three orders of magnitude, we found that collectively, they form a steady-state clone size-distribution with a distinctive shape. Our concise model shows that slow HSC differentiation followed by fast progenitor growth is responsible for the observed broad clone size-distribution. Although all cells are assumed to be statistically identical, analogous to a neutral theory for the different clone lineages, our mathematical approach captures the intrinsic variability in the times to HSC differentiation after transplantation. Steady-state solutions of our model show that the predicted clone size-distribution is sensitive to only two combinations of parameters. By fitting the measured clone size-distributions to our mechanistic model, we estimate both the effective HSC differentiation rate and the number of active HSCs.

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Accelerating immune reconstitution after hematopoietic stem cell transplantation

Cited by 10 publications

References 94 publications

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques

Adoptive T‐cell immunotherapy for ganciclovir‐resistant CMV disease after lung transplantation

Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaque

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