Immunobiology of Cellular Transplantation

The goal of cellular transplantation is to allow long-term function of the grafted cells using minimal host immunosuppression. To this end, the major strategies to implant cells and tissues are through: (i) the pretreatment of the graft to reduce tissue immunogenicity; (ii) the application of immunoisolation technologies to prevent host sensitization to implanted cells; and (iii) the induction of immunological tolerance to the donor tissues. Further, a major dilemma facing clinical tissue grafting is the shortage of donor tissue for transplantation. This problem requires the consideration of tissues from other species (xenografts) as a potential source of donor material. In light of these issues, the focus of this discussion is on the T cell-dependent response to allogeneic and xenogeneic transplants and the implications of this reactivity on the field of cellular replacement therapy.

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Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice

Blood Advances ◽

10.1182/bloodadvances.2021004451 ◽

2021 ◽

Author(s):

Katrien Pletinckx ◽

Kirsty S Nicolson ◽

Heather B Streeter ◽

William J Sanderson ◽

Evelien Schurgers ◽

...

Keyword(s):

T Cell ◽

Replacement Therapy ◽

Immune Tolerance ◽

Neutralizing Antibodies ◽

Antigen Processing ◽

Specific Immunotherapy ◽

Tolerance Induction ◽

Human Leukocyte ◽

Immunological Tolerance ◽

Fviii Inhibitor

Haemophilia A (HA) is a blood clotting disorder caused by various genetic deficiencies in the factor VIII (FVIII) encoding F8 gene. Patients receiving FVIII replacement therapy are at risk of developing neutralizing antibodies (FVIII inhibitors) rendering the FVIII replacement therapy ineffective. Immunological tolerance towards FVIII can be achieved through immune tolerance induction (ITI) protocols in some patients but this is a lengthy and costly desensitization programme. Long-term eradication of inhibitors in HA patients could be achieved by antigen-specific immunotherapy targeting CD4+ T cells since formation of FVIII inhibitors is T cell dependent. Here, we report a peptide-based, antigen-specific immunotherapy designed to specifically re-establish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified two FVIII immunodominant peptides in immunised human leukocyte antigen (HLA) DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimised for tolerogenicity. These modified peptide analogues were initially screened for recognition using FVIII-specific T cell hybridoma clones from FVIII-immunised HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1*haplotypes. The combination of these two FVIII apitopes (ATX-F8-117), administered according to a dose escalation protocol, promoted T cell tolerance towards FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates both anti-FVIII T cell and B cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to both suppress and treat inhibitor formation in susceptible HA patients.

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Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

Blood ◽

10.1182/blood-2016-12-758961 ◽

2017 ◽

Vol 130 (4) ◽

pp. 478-488 ◽

Cited By ~ 9

Author(s):

Pedro M. Rodrigues ◽

Ana R. Ribeiro ◽

Chiara Perrod ◽

Jonathan J. M. Landry ◽

Leonor Araújo ◽

...

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Thymic Epithelial Cells ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Term Function ◽

Key Points

Key Points TEC-intrinsic ablation of p53 predominantly affects medullary TECs, altering their RANK-driven differentiation and transcriptome. Loss of p53 in TECs couples disrupted thymopoiesis to altered T-cell homeostasis and tolerance.

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