Research Highlights : Transplantation

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Research Highlights

Anwar, Imran J. MD1; Luo, Xunrong MD, PhD2

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doi: 10.1097/TP.0000000000004407
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CD11b Suppresses TLR Activation of Nonclassical Monocytes to Reduce Primary Graft Dysfunction After Lung Transplantation

Querrey M, Chiu S, Lecuona E, et al. J Clin Invest. 2022;132(14):e157262.

Early neutrophil infiltration to the lung allograft is the main driver of primary graft dysfunction (PGD) in lung transplantation. However, the signals for chemotaxis of such neutrophil infiltrates are less well understood and thought to originate from donor nonclassical monocytes (NCMs) that reside in the lung allograft.1 Consequently, depletion of NCMs before lung transplantation reduces neutrophil recruitment to the allograft and ameliorate PGD.

In this study, Querrey et al2 investigated the signals that regulate neutrophil chemotaxis during lung transplantation. The authors first demonstrated that CD11b on NCMs plays an inhibitory role in the production of the neutrophil chemoattractant CXCL2 in response to toll-like receptor (TLR) signaling. This interaction resulted in a much-enhanced CXCL2 release in response to TLR2, 4, and 9 agonists by NCMs from mice genetically deficient in CD11b (Itgam–/– mice). Moreover, the transplantation of Itgam–/– donor lungs resulted in a significant increase of neutrophil infiltration and worsened parameters indicative of PGD. Next, the authors demonstrated that both TLR2 and TLR4 could mediate TLR agonist-mediated stimulation of CXCL2 production in NCMs and subsequent neutrophil chemotaxis after lung transplantation. As such, donor lungs from Tlr2–/–Tlr4–/– double knockout or mice with NCM-specific Myd88 deficiency showed reduced neutrophil infiltration in comparison with wild-type donor lungs. The study further showed HMGB1 as a critical TLR agonist, triggering NCM CXCL2 production after lung transplantation. The importance of this TLR agonist was further supported by its elevated serum levels after lung transplantation in human recipients. Finally, either inhibiting HMGB1 with a small molecule inhibitor in both donors and recipients or targeting CD11b by a CD11b agonist in donors resulted in significantly reduced neutrophil recruitment to the lung allograft and reduced PGD severity.

This study elegantly dissected the role of CD11b signaling in NCMs through TLR ligands because it pertains to PGD in lung transplantation. The authors raise interesting perspectives and further questions on targeting donor NCMs to reduce PGD. First, in the rapidly advancing era of ex vivo lung perfusion, it will be highly relevant in clinical lung transplantation to best use this information to amplify CD11b and inhibit TLR signaling in NCMs. It is possible that dual targeting will lead to synergistic benefits. It is also possible that CD11b signaling may have a different consequence in other cells than in NCMs that may require targeted delivery of the CD11b agonist specifically to NCMs. Second, previous work from this group has demonstrated that depletion of donor NCMs in lungs, in fact, ameliorated PGD, suggesting that NCMs likely have roles in PGD other than acting as a brake for CXCL2 production through agonizing CD11b signaling. The relative importance of these factors in contributing to PGD warrants further investigation. Finally, the importance of recipient factors in PGD is evident by the significantly exacerbated PGD rate in recipients of the coronavirus disease 2019 cohort.3 Exactly what recipient factors may interact with donor NCMs (or other cell populations) and the role of CD11b or TLR ligands in these interactions will be imminently necessary to examine.

In summary, this study identified a surprising role of donor CD11b in mediating TLR signaling-promoted PGD in lung transplantation, potentially revealing a therapeutic target for ameliorating this devastating complication in lung transplantation.

Host-versus-commensal Immune Responses Participate in the Rejection of Colonized Solid Organ Transplants

Pirozzolo I, Sepulveda M, Chen L, et al. J Clin Invest. 2022;132(17):e153403.

It has been previously shown that transplantation of barrier organs that contain commensal microbiota has shorter graft survival linked to an enhanced alloimmune response.1 However, the discrete effect of anticommensal immune response and alloimmunity of a host that is to the detriment of commensal microbiota-colonized allografts is not known.

In the present study, Pirozzolo et al2 developed a set of elegant murine transplant models to analyze the role of host-versus-commensal and host-versus-donor immune responses. Their models primarily involved Staphylococcus epidermidis–colonized skin syngeneic or allogeneic transplantation in recipients who were either naive or possessed memory immunity to S epidermidis. Using this approach, they first demonstrated that naive recipients readily mounted a T-cell response to commensals on donor skin allograft even in a syngeneic strain combination. This response was demonstrated by S epidermidis–specific CD8+ TCR-transgenic T cells proliferating in graft draining lymph nodes followed by their migration to the graft itself. Interestingly, this commensal-specific T-cell response transiently damaged the skin graft, manifesting as a combination of hair loss, pigment development, shrinkage of graft size,and development of red inflamed spots. Following eradication of the commensal by T-cell immunity, the damaged graft then repaired itself completely. The necessity of T cell–mediated immunity in this process was demonstrated by the inability of TCR-α knockout recipients genetically devoid of αβ T cells to mount any damage to commensal-colonized syngeneic skin grafts, although the roles of CD4 and CD8 T cells in the process were shown to be redundant and either one was sufficient for graft damage. More interestingly, the authors demonstrated that commensal-specific memory T cells in hosts with prior memory response to the commensal trafficked to the skin grafts, mounting more severe damage to the skin graft. In an allogeneic skin transplant model, Pirozzolo et al further demonstrated that these memory T cells accelerated rejection of commensal-colonized allogeneic skin grafts and were resistant to conventional immunosuppression.

This study convincingly demonstrated that host-versus-commensal T-cell immunity contributes to the damage of skin allografts, acting in parallel to host-versus-donor T-cell immunity to exacerbate colonized skin allograft rejection. Importantly, this work demonstrated that memory host-versus-commensal T-cell immunity, which can be highly prevalent in human transplant recipients, is resistant to conventional immunosuppression. This study also raises several important questions. First, how would findings in this study be generalized to host-versus-commensal T-cell immunity toward other more commonly encountered commensals in organ transplantation including viruses? As different barrier organs carry distinct commensals, studies of the role of such immunity toward a wide spectrum of commensals will be highly informative for devising therapeutic strategies. Second, how may donor tissue-resident innate and/or adaptive immune cells that accompany transplanted organs contribute to the rejection of colonized organs? This is of relevance because some of these donor tissue-resident cells have been shown to persist for a long time after transplantation.3 Finally, to what extent do graft sterilization or conventional depleting induction therapies dampen the attack of colonized allografts by host-versus-commensal immunity?

In summary, this study mechanistically dissected challenges arising from host-versus-commensal immunity in transplantation, pointing to potential prophylactic measures in ameliorating alloimmune responses to barrier organ transplants.


1. Zheng Z, Chiu S, Akbarpour M, et al. Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci Transl Med. 2017;9:eaal4508.
2. Querrey M, Chiu S, Lecuona E, et al. CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation. J Clin Invest. 2022;132:e157262.
3. Kurihara C, Manerikar A, Querrey M, et al. Clinical characteristics and outcomes of patients with COVID-19-associated acute respiratory distress syndrome who underwent lung transplant. JAMA. 2022;327:652–661.


1. Lei YM, Chen L, Wang Y, et al. The composition of the microbiota modulates allograft rejection. J Clin Invest. 2016;126:2736–2744.
2. Pirozzolo I, Sepulveda M, Chen L, et al. Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants. J Clin Invest. 2022;132:e153403.
3. Malone AF, Wu H, Fronick C, et al. Harnessing expressed single nucleotide variation and single cell RNA sequencing to define immune cell chimerism in the rejecting kidney transplant. J Am Soc Nephrol. 2020;31:1977–1986.
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