Graft-Versus-Host Disease Following Liver Transplantation: Development of a High-Incidence Rat Model and a Selective Prevention Method

Abstract

Graft-versus-host disease (GvHD) following liver transplantation (LT) is a rare but serious complication with no presently available animal model and no preventive measures. To develop a rat model of GvHD after LT (LT-GvHD), we preconditioned hosts with sublethal irradiation plus reduction of natural killer (NK) cells with anti-CD8α mAb treatment, which invariably resulted in acute LT-GvHD. Compared with those in the peripheral counterpart, graft CD4 CD25 passenger T cells showed lower alloreactivities in mixed leukocyte culture. Immunohistology revealed that donor CD4 T cells migrated and formed clusters with host dendritic cells in secondary lymphoid organs, with early expansion and subsequent accumulation in target organs. For selectively preventing GvHD, donor livers were perfused ex vivo with organ preservation media containing anti-TCRαβ mAb. T cell-depleted livers almost completely suppressed clinical GvHD such that host rats survived for >100 days. Our results showed that passenger T cells could develop typical LT-GvHD if resistant cells such as host radiosensitive cells and host radioresistant NK cells were suppressed. Selective ex vivo T cell depletion prevented LT-GvHD without affecting host immunity or graft function. This method might be applicable to clinical LT in prediagnosed high-risk donor-recipient combinations and for analyzing immunoregulatory mechanisms of the liver.

Targeted Delivery of Neutralizing Anti-C5 Antibody to Renal Endothelium Prevents Complement-Dependent Tissue Damage

“…Conversely, C5 inhibition failed to prevent IRI in Lewis rats raising the possibility that the involvement of the late C components in mediating renal IR may vary in different species (42). Our finding that C5 neutralization by Ergidina correlates with the prevention of renal IRI in Wistar rats does not support this hypothesis in agreement with recent data showing that antibody-mediated C5 inhibition markedly reduces tissue damage after reperfusion and prolongs graft survival in a syngeneic rat model of kidney transplantation (44). …”

“…The enhanced ex vivo binding to surgically removed kidney exposed to cold ischemia for 24 h followed by perfusion with the recombinant molecule supports its first therapeutic use to prevent posttransplant IRI, leading to delay of graft function. The contribution of C to this pathologic condition is suggested by the beneficial effect obtained perfusing the kidney with other C inhibitors including the membrane-binding C regulator APT070 (46) and, more recently, an anti-rat C5 (44) prior to transplantation. The finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this membrane-binding anti-C5 antibody may represent a useful tool to treat surgically removed organs prior to transplantation to prevent posttransplant IRI.…”

Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen

“…Notably, the stem cells were relatively resistant to the mAb treatment and their hematopoietic activity recovered quickly. Thus, we suggest that DST-antibodies may also be applicable for the suppression of GvHD in patients following allogeneic hematopoietic stem cell transplantation or liver transplantation (18). …”

“…To examine the therapeutic effect of DST on GvHD, recipient rats received a purified IgM mAb against donor RT1.A a , which was newly prepared in this study (DST IgM mAb), 4 or 7 days after the induction of GvHD. We defined rat survival time as the time from the start of the experiment to the time that we observed body weight loss of >10% in 3 days, plus an additional 5 days, which we assumed they would have survived (18). Rats were euthanized 1 day before this defined survival time.…”

Rapid immunosurveillance by recirculating lymphocytes in the rat intestine: critical role of unsulfated sialyl-Lewis X on high endothelial venules of the Peyer’s patches

“…To avoid imposing great stress, the subject rats were cared for dedicatedly during cannulation. An actual body weight (BW) loss after 72-h cannulation was 13.4 ± 2.4% ( n = 6), which was much less than those of wasting conditions such as in rats developing acute graft-versus-host disease (GvHD), where their BW rapidly dropped >30% in 3 days ( 4 ). After counting the hourly output of total lymphocytes, cytospot smears were prepared.…”