Limits...
Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

Denning WL, Xu J, Guo S, Klug CA, Hel Z - PLoS ONE (2011)

Bottom Line: Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model.Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting.Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Harnessing the ability of cytotoxic T lymphocytes (CTLs) to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs) following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

Show MeSH

Related in: MedlinePlus

Immunization with genetically modified HSCs results in protection against a growth of a model thymoma.Mice were immunized with 2×104 HSC-tOVA cells following BU pre-treatment or 2×104 immunodominant OVA peptide-coated DCs. (A) Percentages of OVA-specific CD8+ T cells in blood were monitored by OVA-specific MHC-I pentamer staining. (B) 16 weeks post immunization, mice were inoculated s.c. with 106 E.G7 thymoma cells expressing OVA. Tumor growth was monitored until mice became moribund. 4 animals per group; error bars represent standard errors.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3040734&req=5

pone-0016897-g005: Immunization with genetically modified HSCs results in protection against a growth of a model thymoma.Mice were immunized with 2×104 HSC-tOVA cells following BU pre-treatment or 2×104 immunodominant OVA peptide-coated DCs. (A) Percentages of OVA-specific CD8+ T cells in blood were monitored by OVA-specific MHC-I pentamer staining. (B) 16 weeks post immunization, mice were inoculated s.c. with 106 E.G7 thymoma cells expressing OVA. Tumor growth was monitored until mice became moribund. 4 animals per group; error bars represent standard errors.

Mentions: To test the ability of HSC-based immunization to protect against tumor growth, mice were immunized with 2×104 HSC-tOVA or DCs presenting dominant MHC-I-restricted OVA peptide and 16 weeks later challenged with 106 E.G7 thymoma tumor cells expressing OVA antigen administered subcutaneously. While antigen-specific CD8+ T cells were maintained only at low frequencies in DC-immunized animals, immunization with HSCs resulted in an efficient maintenance of specific CTLs up to the time of tumor challenge at week 16 (Fig. 5A). Mice immunized with OVA-transgenic HSCs were able to control tumor growth throughout the observation period significantly better than DC-immunized or control group (Fig. 5B) (p<0.05 and p<0.001 between HSC-tOVA and DC-pOVA and HSC-tOVA and control group, respectively, weeks 24–28; analyzed by RM-ANOVA). At week 28, two of four HSC-OVA immunized mice but only one of four DC-pOVA-immunized and none of four control mice were free of palpable tumor.


Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

Denning WL, Xu J, Guo S, Klug CA, Hel Z - PLoS ONE (2011)

Immunization with genetically modified HSCs results in protection against a growth of a model thymoma.Mice were immunized with 2×104 HSC-tOVA cells following BU pre-treatment or 2×104 immunodominant OVA peptide-coated DCs. (A) Percentages of OVA-specific CD8+ T cells in blood were monitored by OVA-specific MHC-I pentamer staining. (B) 16 weeks post immunization, mice were inoculated s.c. with 106 E.G7 thymoma cells expressing OVA. Tumor growth was monitored until mice became moribund. 4 animals per group; error bars represent standard errors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040734&req=5

pone-0016897-g005: Immunization with genetically modified HSCs results in protection against a growth of a model thymoma.Mice were immunized with 2×104 HSC-tOVA cells following BU pre-treatment or 2×104 immunodominant OVA peptide-coated DCs. (A) Percentages of OVA-specific CD8+ T cells in blood were monitored by OVA-specific MHC-I pentamer staining. (B) 16 weeks post immunization, mice were inoculated s.c. with 106 E.G7 thymoma cells expressing OVA. Tumor growth was monitored until mice became moribund. 4 animals per group; error bars represent standard errors.
Mentions: To test the ability of HSC-based immunization to protect against tumor growth, mice were immunized with 2×104 HSC-tOVA or DCs presenting dominant MHC-I-restricted OVA peptide and 16 weeks later challenged with 106 E.G7 thymoma tumor cells expressing OVA antigen administered subcutaneously. While antigen-specific CD8+ T cells were maintained only at low frequencies in DC-immunized animals, immunization with HSCs resulted in an efficient maintenance of specific CTLs up to the time of tumor challenge at week 16 (Fig. 5A). Mice immunized with OVA-transgenic HSCs were able to control tumor growth throughout the observation period significantly better than DC-immunized or control group (Fig. 5B) (p<0.05 and p<0.001 between HSC-tOVA and DC-pOVA and HSC-tOVA and control group, respectively, weeks 24–28; analyzed by RM-ANOVA). At week 28, two of four HSC-OVA immunized mice but only one of four DC-pOVA-immunized and none of four control mice were free of palpable tumor.

Bottom Line: Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model.Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting.Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT
Harnessing the ability of cytotoxic T lymphocytes (CTLs) to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs) following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

Show MeSH
Related in: MedlinePlus