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Comparative Study
. 2011 Jan 1;186(1):230-41.
doi: 10.4049/jimmunol.1002965. Epub 2010 Nov 22.

"VSports手机版" Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells

Hongmei Li  1 , Catherine Matte-Martone, Hung Sheng Tan, Srividhya Venkatesan, Jennifer McNiff, Anthony J Demetris, Dhanpat Jain, Fadi Lakkis, David Rothstein, Warren D Shlomchik
Affiliations
Comparative Study

Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells

Hongmei Li et al. J Immunol. .

Abstract

Graft-versus-host disease (GVHD) is initiated by APCs that prime alloreactive donor T cells. In antipathogen responses, Ag-bearing APCs receive signals through pattern-recognition receptors, including TLRs, which induce the expression of costimulatory molecules and production of inflammatory cytokines, which in turn mold the adaptive T cell response. However, in allogeneic hematopoietic stem cell transplantation (alloSCT), there is no specific pathogen, alloantigen is ubiquitous, and signals that induce APC maturation are undefined VSports手机版. To investigate APC activation in GVHD, we used recipient mice with hematopoietic cells genetically deficient in pathways critical for APC maturation in models in which host APCs are absolutely required. Strikingly, CD8-mediated and CD4-mediated GVHD were similar whether host APCs were wild-type or deficient in MyD88, TRIF, or MyD88 and TRIF, which excludes essential roles for TLRs and IL-1β, the key product of inflammasome activation. Th1 differentiation was if anything augmented when APCs were MyD88/TRIF(-/-), and T cell production of IFN-γ did not require host IL-12. GVHD was also intact when APCs lacked the type I IFNR, which amplifies APC activation pathways that induce type I IFNs. Thus in GVHD, alloreactive T cells can be activated when pathways critical for antipathogen T cell responses are impaired. .

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Figures

Figure 1
Figure 1. Signaling by host TLR4 is not required for GVHD
Lethally irradiated B10.ScNCr (TLR4−/−) and B10.ScNCrXB10/J F1 (TLR4+/−) mice were reconstituted with C3H.SW BM with or without 2×106 purified C3H.SW CD8 cells. (A) Percent weight change. *P<0.05, F1 BM alone vs F1 BM plus CD8 from day 19 onward; **P<0.05 B10.ScNCr BM alone vs B10.ScNCr BM plus CD8 from day 7 onward; no significant difference comparing F1 and B10.ScNCr CD8 recipients at all time points except day 9. (B) Pathology scores. Each symbol is the score from an individual mouse. Horizontal lines represent mean scores. P values are shown below the group labels. Data are from 1 experiment.
Figure 2
Figure 2. Signaling by host CD40 is not required for GVHD
B6 CD40−/− and control B6 mice were irradiated and reconstituted with C3H.SW BM with or without 2×106 purified CD8 cells. Shown are pathology scores of skin, ear, colon and liver. There was significant pathology in all tissues in both wt and CD40−/− recipients, relative to their BM only controls; however there was no difference in any tissue comparing wt and CD40−/− CD8 recipients. Data are combined from 2 independent experiments with similar results.
Figure 3
Figure 3. TLR signaling on recipient APCs is not required for CD8-mediated GVHD
Wt→wt, MyD88−/−→wt, TRIF−/−→wt and DKO→wt BM chimeras were reirradiated and reconstituted with C3H.SW BM with or without 2–3×106 purified C3H.SW CD8+ T cells. (A) Percent weight change (P≥0.5 comparing all CD8 recipient groups at all time points; P<0.05 comparing the percent weight change in wt, MyD88−/−, TRIF−/− or DKO chimera CD8-recipients with the respective BM alone groups beginning on day +26); (B) incidence of skin disease (P≥0.29 comparing any CD8 group to any other CD8 group; P<0.003 comparing incidence of skin disease of each CD8 recipient group with its respective BM alone group); (C) Pathology scores. Data are combined from two independent experiments with similar results.
Figure 4
Figure 4. TLR signaling on recipient APCs is not required for CD4 mediated MHC-mismatched GVHD
(A) Experimental design for B–D. B6bm12 mice were irradiated and reconstituted with 5×106 T cell depleted BM from B6 wt, MyD88−/−, TRIF−/− or DKO donors. Three months later, the chimeras were reirradiated and reconstituted with T cell depleted B6bm12 BM and B6bm12 splenocytes containing 106 CD4 cells. (B) Percent weight change. P values comparing BM alone vs CD4 recipients by host: wt, P<0.05 at day 7; MyD88−/−, P<0.05 from day 7 onward; TRIF−/−, P<0.05 at day 7; DKO, P<0.05 from day 5 onward except day 14 and 16. P<0.05 comparing DKO and wt CD4 recipients, beginning on day 12. (C) Pathology scores from colon and liver. No significant difference comparing wt→B6bm12 CD4 recipients to any other CD4 recipient group. Data in B and C were from one experiment; the number of mice/group is shown in the figure. (D) Serum cytokine levels and representative intracellular IFN-γ staining from chimeric mice transplanted as in (A) at day 7 after BMT. Data from 3 mice per BM alone group. The numbers of mice per CD4 group were as follows: wt, n=10; MyD88−/−, n=5; TRIF−/−, n=5; DKO, n=9. P<0.05, comparing wt, MyD88−/−, TRIF−/− or DKO CD4 recipients to their respective BM only controls for all cytokines. Levels of TNF-α, IFN- γ, GM-CSF and IL-12 were greater in DKO recipients as compared to wt controls (* P<0.05). Data for DKO and wt recipients are combined from two experiments with similar results. B6 wt, DKO, p35−/− and MyD88−/−/IFNAR1−/− mice were irradiated and reconstituted with B6bm12 BM and 5×105 B6bm12 CD4+CD62L+CD44−CD25− T cells. Intracellular IFN-γ staining was performed on splenocytes harvested from mice on day +7 (E; representative data from 6–10 mice per group from at least 2 independent experiments).
Figure 5
Figure 5. Host IFNAR1 is not required for CD8-mediated GVHD in the C3H.SW→B6 strain pair
(A) Percent weight change. *P<0.03, comparing wt BM alone vs CD8 recipients from day 17 onward; **P<0.001, comparing IFNAR1−/− BM alone vs IFNAR1−/− CD8 from day 20 onward; *** P<0.01 comparing wt and IFNAR 1 CD8 recipients from day 13 onward. (B) Incidence of skin disease. P<0.03 comparing wt and IFNAR1−/− CD8 recipients to their BM alone controls; P>0.24 comparing wt and IFNAR1−/− CD8 recipients. (C) Number of skin ulcers. and (D) pathology scores. CD8 recipients had significant pathology in skin, ear, colon and liver relative to their BM alone controls. Data are combined from two independent experiments with similar results.
Figure 6
Figure 6. Comparable GVHD developed in retransplanted IFNAR1−/−→wt and wt→wt BM chimeras
B6 mice were irradiated and reconstituted with BM from wt or IFNAR1−/− mice. Three months later, chimeras were reirradiated and reconstituted with C3H.SW BM with or without purified C3H.SW CD8 cells. (A) Percent weight change. P<0.05 from day +8 onwards comparing wt→wt BM alone vs CD8 recipients. P<0.05 from day +20 onwards comparing IFNAR1−/−→wt BM alone vs CD8 recipients. (B) Incidence of skin disease. P<0.001 comparing wt→wt and IFNAR1−/−→wt CD8 recipients to their respective BM alone controls. P>0.86 comparing CD8 recipient groups. (C) Number of skin ulcers and (D) pathology scores. CD8 recipients had significant pathology in skin, ear, small intestine, colon and liver relative to their BM alone controls. There was no significant differences comparing CD8 recipient groups except for modestly more severe skin and small intestine GVHD in wt→wt and IFNAR1−/−→wt CD8 recipients, respectively. Data are combined from two independent experiments with similar results.
Figure 7
Figure 7. Host B71/B72 or IL-12 are not required for CD8-mediated GVHD in the C3H.SW→B6 model
Pathology scores comparing GVHD in p35−/− (A) and B71/B72−/− (B) as compared to wild type recipients. Shown are data combined from two independent experiments for each in A and B. There were no significant differences comparing wt and p35−/− CD8 recipients except more severe skin (P=0.028) and ear disease (P=0.005) in p35−/− mice. There were no significant differences comparing wt and B71/B72−/− CD8 recipients except more severe skin disease in B71/B72−/− mice (P<0.001).
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"VSports在线直播" References

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