Transplantation Immunology

Transplantation immunology encompasses the mechanisms by which the host’s immune system recognises and either rejects or tolerates genetically distinct grafts. Adaptive immunity drives acute and chronic rejection through T-cell allorecognition of donor-derived major histocompatibility complex (MHC) antigens via three overlapping pathways: direct presentation by donor antigen-presenting cells, indirect presentation of processed donor peptides on host MHC, and semi-direct transfer of intact donor MHC to host dendritic cells. CD8+ cytotoxic T cells induce graft cell apoptosis, while CD4+ T helper subsets (Th1, Th2, Th17 and T follicular helper cells) secrete cytokines that recruit macrophages, neutrophils and B cells. Donor-specific antibodies produced by B cells mediate complement fixation and vascular injury. Memory T cells resist many costimulatory-blockade regimens and drive accelerated rejection. Innate immunity contributes through pattern-recognition receptor sensing of damage-associated molecular patterns released during ischaemia–reperfusion or cell death. Monocytes and neutrophils infiltrate the graft, mature into macrophages or dendritic cells, and amplify T-cell priming. Macrophage polarisation (M1 pro-inflammatory versus M2 reparative) influences graft outcome. Regulatory subsets—including FoxP3+ Tregs, IL-10–producing Bregs, tolerogenic dendritic cells and myeloid-derived suppressor cells—promote antigen-specific tolerance. Clinical immunosuppression aims to inhibit these effector arms while preserving protective immunity.

Research from Nature Portfolio

In a landmark study, genetically engineered porcine kidneys carrying 79 targeted edits—including knockout of key carbohydrate antigens, inactivation of porcine endogenous retroviruses and insertion of human complement-regulatory and anticoagulant genes—were transplanted into non-human primates. Endothelial cells from edited grafts modulated inflammation as effectively as human endothelium, and graft survival was markedly prolonged compared with less-edited controls. This work demonstrates that large-scale genome editing can overcome major innate and adaptive barriers to xenotransplantation.

Complementing xenograft advances, hypoimmune pluripotent stem cells edited to remove class I and II human leucocyte antigens and overexpress immune-evasive molecules survived for months in fully immunocompetent allogeneic macaques without systemic immunosuppression. These cells differentiated in vivo into functional lineages, offering proof of concept for off-the-shelf cell therapies that evade both innate and adaptive host immunity.

Research from all publishers

Monocytes have been shown to discriminate self from allogeneic non-self via polymorphisms in signal-regulatory protein α (SIRPα). This “innate allorecognition” drives monocyte differentiation into dendritic cells within the graft, leading to IL-12 production and activation of alloreactive T cells. Targeting SIRPα-mediated pathways may therefore represent a novel approach to suppress the initiation of adaptive rejection.

In lung transplantation models, ischaemia–reperfusion injury releases damage-associated molecular patterns that rapidly recruit neutrophils into the graft. CCR2+ monocytes and donor-derived alveolar macrophages amplify this influx by producing neutrophil chemoattractants. Neutrophils then cluster with dendritic cells to enhance IL-12 release and expand IFN-γ+ T cells, linking innate injury directly to T-cell-mediated rejection and suggesting new targets to protect lung allografts from early inflammation.

Transplantation Immunology publication trend

The graph below shows the total number of articles in transplantation immunology across all publications each year (not limited to Nature Index journals).

Technical terms

Allorecognition: Detection of non-self MHC antigens by host T cells, via direct, indirect or semi-direct pathways.

Damage-associated molecular patterns (DAMPs): Self-molecules released by injured or necrotic cells that activate innate immune receptors.

Costimulatory blockade: Therapeutic inhibition of T-cell activation signals, for example by CTLA4-Ig, to prevent rejection.

Regulatory T cell (Treg): CD4+CD25+FoxP3+ lymphocyte subset that suppresses immune responses and promotes graft tolerance.

Myeloid-derived suppressor cell (MDSC): Heterogeneous myeloid lineage cells that inhibit T-cell activation and can modulate graft outcomes.

Xenotransplantation: Transplantation of organs, tissues or cells between different species, often using genetically modified pigs to overcome immunological barriers.

References

1. Design and testing of a humanized porcine donor for xenotransplantation. Nature (2023).
2. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nature Biotechnology (2023).
3. Immune Tolerance and Rejection in Organ Transplantation.