Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Coleman, Miranda A.; Bridge, Jennifer A.; Lane, Steven; Dixon, Chantelle M.; Hill, Geoffrey R.; Wells, James W.; Thomas, Ranjeny; Steptoe, Raymond J.

doi:10.1182/blood-2012-06-434100

Cited by 16 publications

(60 citation statements)

References 48 publications

(86 reference statements)

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“…Donor-type leukocyte accumulation, indicating engraftment, was lower in HSPC than BM recipients (Fig. 4A), as anticipated from previous studies (22). However, 5 weeks after HSPC or BM transfer, total spleen cell number did not differ between groups (Fig.…”

Section: Tmem Inactivation Requires Engraftment Of Antigenencoding Hesupporting

confidence: 73%

“…We now advance this to show application to the clinical challenge of b-cell-specific memory T-cell responses that represent a strong impediment to islet graft survival. Previous studies showed when using gene-modified BM transfer that restricting antigen expression to differentiated APCs permitted BM engraftment under immune-preserving conditions in naive and primed recipients (22). However, the fate of established memory T cells was not examined.…”

Section: Discussionmentioning

confidence: 99%

“…6B). Together, these observations were consistent with a pattern of OT-I Tmem expansion followed by deletion in 11c.OVA BM recipients that would be anticipated based on previous studies (22). As host T-cell dynamics after low-dose irradiation might confound this analysis, we tested the contribution of deletion more directly.…”

Section: Deletion Contributes To Ablation Of Cd8mentioning

confidence: 99%

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Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

et al. 2016

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Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by "conventional" therapies, memory T cell-mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell-derived replacement b-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement b-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8 + T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8 + memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigenspecific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized b-cell replacement therapies using patient-derived stem cells.

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Section: Tmem Inactivation Requires Engraftment Of Antigenencoding Hesupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Deletion Contributes To Ablation Of Cd8mentioning

confidence: 99%

See 1 more Smart Citation

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

et al. 2016

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“…Expression of antigens in APC, including DCs, induces T cell tolerance and prevents antigen-specific T cell responses under classical Th1-inducing conditions (23,27). To test this potential under Th2-inducing conditions, mice expressing OVA in DC (DC.OVA) and nontransgenic (non-Tg) controls were i.p.…”

Section: Resultsmentioning

confidence: 99%

“…Transfer of antigen-encoding BM or hematopoietic stem and progenitor cells (HSPC) using mild conditioning transfers a tolerogenic environment to hosts (27) and has therapeutic potential (28). Here, we sought to determine whether this could terminate pathogenic Th2 responses in an allergic airways disease (AAD) setting.…”

Section: Introductionmentioning

confidence: 99%

Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

et al. 2017

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Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy

et al. 2017

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Respiratory allergies represent a significant disease burden worldwide affecting up to 300 million people globally. Medication and avoidance of known triggers do not address the underlying pathology. Traditional immunotherapies for allergy aim to reinstate immune homeostasis but require years of treatment and have poor long-term efficacy. Novel approaches, such as gene-engineered hematopoietic stem cell transplantation, induce profound antigen-specific tolerance in autoimmunity. Recent evidence shows this approach may also have therapeutic utility for allergy. Here, we review the mechanisms of antigen-specific tolerance and the potential of stem cell-mediated gene therapy to induce tolerance in allergic respiratory diseases.

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Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Abstract: Key Points• Restricting transgenic antigen expression to differentiated antigen-presenting cells protects hematopoietic progenitors from immune attack.• Restricting transgenic antigen expression to differentiated antigen-presenting cells promotes tolerogenic outcomes.

Cited by 16 publications

References 48 publications

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy

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