Experimental animal model of graft-versus-host disease (GVHD) after small-bowel transplantation: Characteristics of the model and application to developing treatment strategies

Abstract

Although graft-versus-host disease (GVHD) has been a major concern after small-bowel transplantation (SBTX), the lack of suitable experimental model has allowed only limited study of GVHD after solid-organ transplantation. 1 We recently developed a clinically relevant experimental animal model of GVHD of fully allogeneic SBTX. This study describes histopathological evolution of the disease, cytokine involvement, responsible donor cells, and preliminary results of treatment using recipient and third-party cell infusion. MATERIALS AND METHODSLewis (LEW, RT11) rat recipients received orthotopic SBTX and simultaneous donor bone marrow cell infusion (BMC, 250 × 10 6 ) from ACI (RT1 a ) rats. Tacrolimus (FK 506, 1 mg/kg per day) was administered on days 0 to 13, then continued as a weekly injection of same dose for 350 days. The number of donor cells in the recipient circulation was determined by flow cytometry using antibodies specific for donor and recipient MHC class I (MAbs MN4-91-6 and 163). Reverse-transcription polymerase chain reaction (RT-PCR) using 32 P-labeled primers was used to measure the levels of cytokine mRNA in the graft and recipient tissues. RESULTSDonor cells persisted in the recipients for more than 300 days after transplantation and accounted for 5% to 25% of lymphocytes in the circulation. The gradual increase of donor cells in these animals correlated with the appearance of clinical signs of GVHD (skin rash, hyperkeratosis, body weight, and hair loss) with a median onset of 104 days (range 98 to 114 days). These signs of GVHD waxed and waned for the rest of the experimental period, and eventually all animals died of GVHD or other transplantation-related complication, such as infection, with a median survival of 244 days. Cytokine analysis revealed the association of the histopathological changes of GVHD (grades I-III) and the upregulation of IFN-γ, TNF-α, IL-6, and IL-10 in the cervical lymph nodes and skin before and after animals showing clinical signs of GVHD. However, donor and recipient small bowel in this model did not show any increased expression of cytokine mRNA or histopathological changes.Efficacy of immunomodulatory treatment of GVHD was examined using this GVHD model of SBTX and BMC. In vivo ACI (donor strain)-primed splenocytes were prepared from LEW (recipient strain) or PVG (third-party strain) rats that received simultaneous ACI heart

Modified Multivisceral Transplantation with Native Spleen Removal in Rats

“…10,11 In a classic paper, Monchik and Russel described the occurrence of GVHD-like phenomenon using Lewis to Brown Norway F 1 hybrid strain combination. Murase et al 12 and Galvao et al 13,14 further developed the experimental model of GVHD in the following years; however, these models were based in the genetic immunologic of the different strain combinations. This scene is probably different from what we found in the clinic; therefore, a new model based in the lymphocyte load rather than the genetic predisposition to GVHD would be helpful in the understanding of this severe complication.…”

Control Of Organ Transplant-Associated Graft-versus-Host Disease By Activated Host Lymphocyte Infusions

“…Such T cells usually exhibit alloreactivity without extensive prestimulation. Transfer of unprimed prestored host T cells might therefore be an alternative strategy to the described selection and expansion procedure, albeit a less effective one, as demonstrated in an experimental GvHD model after small-bowel transplantation (5).…”

Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation

“…It is also important to consider the higher weight and strength of Lewis rats compared with BN rats of the same age, which are more labile and vulnerable, which is crucial to know when planning a difficult postoperative period. Based on previous studies, Ye et al described a similar GVHD model with ACI-Lewis combination rats, although they also did not provide details [76,[78][79][80][81][82][83].…”