Improving thymus implantation for congenital athymia with interleukin-7.

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2023-01

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Abstract

Objectives

Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.

Methods

Using Foxn1 nu athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus.

Results

We determined that thymus implants in Foxn1 nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into Foxn1 nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.

Conclusion

We conclude that implanting cultured thymus into the muscle of Foxn1 nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL-7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.

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10.1002/cti2.1475

Publication Info

Min, Hyunjung, Laura A Valente, Li Xu, Shane M O'Neil, Lauren R Begg, Joanne Kurtzberg and Anthony J Filiano (2023). Improving thymus implantation for congenital athymia with interleukin-7. Clinical & translational immunology, 12(11). p. e1475. 10.1002/cti2.1475 Retrieved from https://hdl.handle.net/10161/29434.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Kurtzberg

Joanne Kurtzberg

Jerome S. Harris Distinguished Professor of Pediatrics

Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology, pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation, and novel applications of cord blood and birthing tissues in the emerging fields of cellular therapies and regenerative medicine.   Dr. Kurtzberg serves as the Director of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant and Cellular Therapy Program, Director of the Carolinas Cord Blood Bank, and Co-Director of the Stem Cell Transplant Laboratory at Duke University.  The Carolinas Cord Blood Bank is an FDA licensed public cord blood bank distributing unrelated cord blood units for donors for hematopoietic stem cell transplantation (HSCT) through the CW Bill Young Cell Transplantation Program.  The Robertson GMP Cell Manufacturing Laboratory supports manufacturing of RETHYMIC (BLA, Enzyvant, 2021), allogeneic cord tissue derived and bone marrow derived mesenchymal stromal cells (MSCs), and DUOC, a microglial/macrophage cell derived from cord blood.

Dr. Kurtzberg’s research in MC3 focuses on translational studies from bench to bedside, seeking to develop transformative clinical therapies using cells, tissues, molecules, genes, and biomaterials to treat diseases and injuries that currently lack effective treatments. Recent areas of investigation in MC3 include clinical trials investigating the safety and efficacy of autologous and allogeneic cord blood in children with neonatal brain injury – hypoxic ischemic encephalopathy (HIE), cerebral palsy (CP), and autism. Clinical trials testing allogeneic cord blood are also being conducted in adults with acute ischemic stroke. Clinical trials optimizing manufacturing and testing the safety and efficacy of cord tissue MSCs in children with autism, CP and HIE and adults with COVID-lung disease are underway. DUOC, given intrathecally, is under study in children with leukodystrophies and adults with primary progressive multiple sclerosis.

In the past, Dr. Kurtzberg has developed novel chemotherapeutic drugs for acute leukemias, assays enumerating ALDH bright cells to predict cord blood unit potency, methods of cord blood expansion, potency assays for targeted cell and tissue based therapies. Dr. Kurtzberg currently holds several INDs for investigational clinical trials from the FDA.  She has also trained numerous medical students, residents, clinical and post-doctoral fellows over the course of her career.

Filiano

Anthony J Filiano

Assistant Professor in Neurosurgery

Immune dysfunction has been described in most neurological disorders. Preclinical strategies targeting these disorders have primarily concentrated on directly targeting synaptic function; however, most of these approaches have failed. Our lab is interested in understanding the complex interactions between the immune system and nervous system with the intent to uncover novel therapeutic targets to combat diseases such as autism spectrum disorder.

 Projects in the Lab:

  1. T cells support proper brain function and mice lacking T cells have behavioral deficits, such as decreased learning and memory and social withdrawal. Further, alterations in T cell function have been described in many neurological disorders. Interestingly, T cells are not present in the parenchyma of a healthy brain; yet they patrol the meninges and likely influence neuronal activity via the release of soluble cytokines. We are investigating how cytokines, and other immune-cell derived molecules, can regulate neural circuits and how an imbalance in these molecules might affect the brain in autism spectrum and other related disorders.               
  2. Cord blood contains a rich source of immune-modulating components including, stem cells, immune cells, and soluble factors. Recent work has demonstrated the efficacy of using cord-blood derived components to promote myelination and increase function in neurological conditions such as multiple sclerosis, autism spectrum disorder, and aging. We are investigating how cord-blood derived cells and products can be used to promote healthy brain function and alleviate behavioral dysfunction in these devastating neurological conditions.

 


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