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Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants
Isabella Pirozzolo, … , Anita S. Chong, Maria-Luisa Alegre
Isabella Pirozzolo, … , Anita S. Chong, Maria-Luisa Alegre
Published July 14, 2022
Citation Information: J Clin Invest. 2022;132(17):e153403. https://doi.org/10.1172/JCI153403.
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Research Article Immunology

Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants

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Abstract

Solid organ transplantation is the preferred treatment for end-stage organ failure. Although transplant recipients take life-long immunosuppressive drugs, a substantial percentage of them still reject their allografts. Strikingly, barrier organs colonized with microbiota have significantly shorter half-lives than non-barrier transplanted organs, even in immunosuppressed hosts. We previously demonstrated that skin allografts monocolonized with the common human commensal Staphylococcus epidermidis (S.epi) are rejected faster than germ-free (GF) allografts in mice because the presence of S.epi augments the effector alloimmune response locally in the graft. Here, we tested whether host immune responses against graft-resident commensal microbes, including S.epi, can damage colonized grafts independently from the alloresponse. Naive hosts mounted an anticommensal T cell response to colonized, but not GF, syngeneic skin grafts. Whereas naive antigraft commensal T cells modestly damaged colonized syngeneic skin grafts, hosts with prior anticommensal T cell memory mounted a post-transplant immune response against graft-resident commensals that significantly damaged colonized, syngeneic skin grafts. Importantly, allograft recipients harboring this host-versus-commensal immune response resisted immunosuppression. The dual effects of host-versus-commensal and host-versus-allograft responses may partially explain why colonized organs have poorer outcomes than sterile organs in the clinic.

Authors

Isabella Pirozzolo, Martin Sepulveda, Luqiu Chen, Ying Wang, Yuk Man Lei, Zhipeng Li, Rena Li, Husain Sattar, Betty Theriault, Yasmine Belkaid, Anita S. Chong, Maria-Luisa Alegre

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Figure 2

Hosts with memory against commensals present on donated organs damage colonized syngeneic skin grafts.

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Hosts with memory against commensals present on donated organs damage co...
(A) Hosts were injected with S.epi (1 × 105 CFU s.c.) 30, 28, and 25 days before receiving S.epi-monocolonized syngeneic skin grafts. Grafts were scored on a 4-point scale (see Figure 1D). (B) Endogenous S.epi-specific T cells in the skin and SDLNs 1 month after S.epi immunization. Gated on CD45.2+TCRβ+CD8+CD4–CD44+ H2-M3:fMIIINA–PE+ (tetramer against S.epi-reactive T cells) events. Plots show fold change relative to unimmunized mice (mean ± SEM) analyzed by Wilcoxon’s log-rank test. (C) Graft scores of syngeneic hosts with or without anti-S.epi memory that received GF or S.epi-monocolonized skin grafts (green line is also shown in Figure 1E). (D) H&E-stained sections from S.epi-monocolonized syngeneic grafts in hosts with anti-S.epi memory or a syngeneic, uncolonized graft in a naive host. A blinded pathologist identified (black arrows) and quantified (purple bars) abnormal mixed lymphocytic/neutrophilic infiltrates around hair follicles. Quantifications are plotted with the macroscopic 4-point score of the graft at sacrifice (orange bars). Original magnification ×20. (E) PCR band intensities of S.epi DNA isolated from skin swabs of S.epi-painted SPF hosts naive to (green) or with memory against (orange) S.epi. Intensities are normalized to a S.epi-positive control. An unpaired, 2-tailed t test was performed at each time point. (F) Graft scores of syngeneic hosts with or without anti–S. aureus memory that received skin grafts from SPF donors with or without S. aureus colonization. (C, E, and F) The area under the graft score curves was calculated for each mouse, and ANOVA with multiple comparisons was performed. Plots show 1 (F), 2 (E), 3 (B and C, green and blue lines), or 4 (C, orange line) independent experiments. **P < 0.005, ***P < 0.0005; mem., memory; col., colonized; d, day; ND, no data.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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