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Review
. 2025 Jul 1;31(4):404-408.
doi: 10.1097/MCP.0000000000001180. Epub 2025 May 21.

The search for peripheral tolerance in lung transplantation

Mark E Snyder  1   2 , John F McDyer  1   2
Affiliations
Review

The search for peripheral tolerance in lung transplantation

Mark E Snyder et al. Curr Opin Pulm Med. .

Abstract

Purpose of review: Median survival after lung transplantation is 5.7 years, which lags behind other solid organ transplants, such as heart, liver, and kidney. The major barrier to long-term survival in lung transplant recipients is chronic lung allograft dysfunction (CLAD). This review discusses the challenge of CLAD as a barrier to tolerance and identifies key areas in the field that require further development.

Recent findings: CLAD is a heterogenous disease in its kinetics of onset and severity and remains a clinical diagnosis of exclusion, based on a decline in allograft function. While acute cellular rejection and antibody-mediated rejection are major risk-factors for CLAD, other barriers to long-term allograft acceptance are aspiration and primary graft dysfunction. However infections, particularly respiratory viral infections and Cytomegalovirus (CMV) remain the most significant risks for CLAD. Additionally, the lung transplant field is limited by a lack of molecular diagnostic assays for CLAD. Further, new targets are needed for precision immunosuppression, and more studies are needed to develop novel interventions to extend allograft acceptance.

Summary: This review discusses new lines of study to address important unmet needs necessary to extend lung allograft acceptance. Other studies, such as tandem lung transplant and bone marrow transplant in select patients with primary immunodeficiency may provide additional lessons on how to potentially establish tolerance. However, tolerance in lung transplant is extremely rare, and further studies are needed to pursue this ultimate goal.

Keywords: allograft rejection; chronic lung allograft dysfunction; lung transplant; tolerance.

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References

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    1. Moghbeli K, Lipp MA, Bueno M, et al. NKG2D blockade impairs tissue-resident memory T cell accumulation and reduces chronic lung allograft dysfunction. JCI Insight 2025; 10:e184048.

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