Features Of Chronic Rejection Research Articles

Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts

BackgroundThe major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice. MethodsC57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively. ResultsTracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment. ConclusionReceptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.

Sodium Sulfite Exacerbates Allograft Vasculopathy and Affects Tryptophan Breakdown in Murine Heterotopic Aortic Transplantation

Graft vasculopathy is the main feature of chronic rejection in organ transplantation, with oxidative stress being a major trigger. Inflammation-associated prooxidant processes may be controlled by antioxidants; however, interference with redox-regulated mechanisms is a complex endeavor. An essential feature of the cellular immune response is the acceleration of tryptophan (Trp) breakdown, leading to the formation of several bioactive catabolites. Long-term activation of this immunobiochemical pathway contributes to the establishment of a tolerogenic environment, thereby supporting allograft survival. Herein, the impact of the antioxidant sodium sulfite on the development of graft vasculopathy was assessed in murine aortic transplantation. Allogeneic (BALB/c to C57BL/6) heterotopic murine aortic transplantations were performed. Animals were left untreated or were treated with 10 μl of 0.1 M, of 0.01 M sodium sulfite, or of 0.1 M sodium sulfate, intraperitoneally once/day, until postoperative day (POD) 100. Grafts were assessed by histology, immunohistochemistry, and adhesion molecule gene expression. Serum concentrations of tryptophan and its catabolite kynurenine (Kyn) were measured. On day 100, graft vasculopathy was significantly increased upon treatment with 0.1 M sodium sulfite, compared to allogeneic untreated controls (p = 0.004), which correlated with a significant increase of α-smooth-muscle-actin, Vcam-1, and P-selectin. Serum Kyn concentrations increased in the allogeneic control group over time (p < 0.05, POD ≥ 50), while low-dose sodium sulfite treatment (0.01 M) treatment resulted in a decrease in Kyn levels over time (p < 0.05, POD ≥ 10), compared to the respective baselines (p < 0.05). Longitudinal analysis of serum metabolite concentrations in the different treatment groups further identified an overall effect of sodium sulfite on Kyn concentrations. Antioxidative treatment may result in ambivalent consequences. Our data reveal that an excess of antioxidants like sodium sulfite can aggravate allograft vasculopathy, which further highlights the challenges associated with interventions that interfere with the complex interplay of redox-regulated inflammatory processes.

Novel immunological and clinical insights in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is a promising approach to restore the quality of life of carefully selected patients that suffered extensive injury. Although acute rejection occurs very frequently, still little is known about the specific characteristics of the VCA immune response. This review aims to highlight the current development in the field of VCA concerning the immunobiology and management of upper extremity and face transplant recipients. T-cell mediated rejection is the predominant mechanism of allograft injury in VCA. As current histological classification does not differentiate types of rejection, novel evidence using NanoString has determined a molecular signature that helps identify antibody-mediated rejection in comparison to T-cell mediated rejection. Additionally, long-term follow-up of VCA patients progressively reveals various features of chronic rejection, and novel immunosuppressive approaches such as costimulation blockade found its way into immunosuppressive regimens of VCA recipients, unraveling its potential benefits as well as limitations. Finally, novel noninvasive biomarkers were recently evaluated and showed promise to differentiate the severity of acute rejection, and consequently, the intensity of treatment required. With growing knowledge about the immunobiology in VCA, novel approaches to immunosuppressive therapy and immune monitoring will help better manage patients and improve long-term VCA outcomes.

Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model

BackgroundJanus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. MethodsLewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated. ResultsAS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial–mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts. ConclusionsThese results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

Six-Month Feeding of Low-Dose Fish Oil Decreases Vascular Expression of High Mobility Group Box1 and Receptor for Advanced Glycation End-Products in Rat Chronic Allograft Vasculopathy

Chronic allograft vasculopathy (CAV) is a typical feature of chronic rejection of small bowel transplantations (SBTx). Our previous studies revealed that feeding fish oil, a natural source of n-3 polyunsaturated fatty acids (PUFAs), protected against CAV. The underlying mechanism remains to be clarified. The pathway mediated by the receptor for advanced glycation end products (RAGE) and its ligand, high mobility group box-1 (HMGB1), which may contribute to the pathogenesis of CAV, is potentially regulated by n-3 PUFAs. Using a chronic rejection model of rat SBTx, the present study investigated whether amelioration of CAV by fish oil feeding was associated with regulation of the RAGE signaling pathway. Moreover, our previous studies also showed that feeding low-dose fish oil for 3 months had no effect. Since an relatively short duration of treatment might fail to produce a visible response, we fed low-dose fish oil for 190 postoperative days. Male inbred Lewis rats and F344 rats were used to establish a chronic rejection model of SBTx. The recipient rats were administered phosphate-buffered saline or fish oil at a daily dose of 3 mL/kg. All rats survived over 190 postoperative days. The expression of HMGB1 and RAGE increased in CAV-bearing vessels. Feeding low-dose fish oil for 6 months attenuated CAV, and significantly reduced HMGB1 and RAGE expressions, indicating beneficial effects of low-dose fish oil on CAV may occur via down-regulation of the HMGB1-RAGE pathway.

Attenuation of Transplant Arteriosclerosis by Oral Feeding of MHC Encoding Chitosan-DNA Nanoparticles Is Mediated by Humoral Immunity

Purpose One promising approach for the induction of transplant tolerance is the pre-treatment of transplant recipients with donor MHC-alloantigen. Our study focuses on the oral delivery of MHC-antigen encoding genes via chitosan-DNA nanoparticles to modulate the allo-immune response in order to reduce the development of transplant arteriosclerosis, the hallmark feature of chronic rejection after heart transplantation. Methods and Materials We performed fully allogeneic mouse abdominal aortic transplantats using C57BL/6 (H2 b ) mice as donors and CBA.J (H2 k ) mice as recipients Aortic grafts were analyzed by histology and morphometry on day 30 after transplantation, levels of circulating alloantibodies were detected by FACS analysis. Results Pre-treatment of recipient mice with chitosan-DNA nanoparticles encoding for K b , one of the MHC-I molecules of the donor, resulted in a significant reduction of intimal proliferation compared to untreated controls. When Ovalbumin was fed instead of K b encoding nanoparticles (K b -NP) or Balb/c (H2 d ) grafts were used instead of C57BL/6 (H2 b ) grafts as antigen controls, both groups showed no reduction of intimal thickness indicating an antigen-specific mechanism. In addition, analysis of peripheral blood of the transplanted mice showed significant suppression of alloantibody formation in the K b -NP fed group compared to all other allogeneic transplanted groups suggesting modulation of the humoral immune response. Conclusions These results demonstrate the potential of chitosan-DNA nanoparticles to induce K b -specific tolerance and to reduce the development of transplant arteriosclerosis.

The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys

The mechanism of chronic rejection of transplanted human kidneys is unknown. An understanding of this process is important because, chronic rejection ultimately leads to loss of the kidney allograft in most transplants. One feature of chronic rejection is the infiltration of ectopic B-cell clusters that are clonal into the transplanted kidney. We now show that the antibodies produced by these B-cells react strongly with the core carbohydrate region of LPS. Since LPS is a costimulatory immunogen that can react with both the B-cell receptor (BCR) and the Toll-like receptor 4 (TLR4), these results suggest a mechanism for the selective pressure that leads to clonality of these B-cell clusters and opens the possibility that infection and the attendant exposure to LPS plays a role in the chronic rejection of human kidney transplants. If confirmed by clinical studies, these results suggest that treating patients with signs of chronic rejection with antibiotics may improve kidney allograft survival.

Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.

Thickening of the Peritubular Capillary Basement Membrane Is a Useful Diagnostic Marker of Chronic Rejection in Renal Allografts

In kidney transplantation, the multilayering of the peritubular capillary basement membrane (MLPTC) in electron microscopy (EM) has been recognized as a feature of chronic rejection (CR). In this study, thickening of the peritubular capillary (PTC) basement membrane was evaluated by light microscopy (LM) to determine whether it corresponds to the MLPTC in EM and whether it can be used as a diagnostic marker of CR. Forty-eight patients with late renal allograft were divided into chronic allograft nephropathy (CAN) with CR (Group 1, n = 23), CAN without CR (Group 2, n = 19) and CAN-free (Group 3, n = 6). The thickening of the PTC basement membrane (ptcbm) was scored from grades 0 to 2 (ptcbm score), and the MLPTC thickness was measured in EM. Interobserver agreement on ptcbm scores was statistically significant (Kappa coefficient = 0.63). LM and EM lesions corresponded very well. The ptcbm score was highest in Group 1, and ptcbm2 corresponded closely with CR. Group 1 showed significantly thicker MLPTC than Groups 2 and 3. The results validated the usefulness of the ptcbm score and suggested that the thickening of the PTC basement membrane can be a novel diagnostic marker of CR.

Features of chronic allograft rejection on rat small intestine transplantation

The aim of this study was to develop a model of chronic rejection of the entire small intestine transplantation and to analyze the features of chronic rejection. Allogenic small bowel transplantation was performed in a rat combination of Lewis to F344. Intestines were procured at the 60th and the 90th day after operation. We compared the semiquantitative score of histological parameters. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining and the cytokine levels in grafts. The significant characteristics of the allograft on histology were changes of villous architecture, interstitial fibrosis, leukocyte infiltration, and obliterative arteriopathy. Allografts on the 60th day post-transplantation had more score in inflammatory events, while the grafts on the 90th day after operation had more values in ischemia/fibrotic events. The number of infiltrating CD4, CD8 and macrophage cells in allografts progressively decreased over time. The level of intragraft cytokines such as IL-6, TNF-alpha and IL-10 in the 90th day after transplantation also decreased compared with that in the 60th day. These data suggested that in the early stage (POD 60), there were more active and intense inflammatory events; later (POD 90) allografts manifested less inflammation and more arterial obliteration and fibrosis.

Hosts Lacking Fms-Like Tyrosine Kinase 3 Ligand Exhibit Marked Reductions in Transplant Vascular Sclerosis

Mice lacking fms-like tyrosine kinase 3 ligand (Flt3L-/-) as the result of targeted gene disruption show severe reductions in dendritic cell (DC) subsets. We examined the development of vascular sclerosis and alloimmune reactivity in wild-type C57BL/6 (B6) and Flt3L-/- B6 (H2b) recipients of aortic allografts from normal BALB/c (H2d) donors. DC deficiency was confirmed by flow cytometric analysis. Aortic allografts were anastomosed to the infrarenal portion of the recipient's abdominal aorta. No immunosuppressive therapy was administered. Transplant outcome was assessed 60 days postgrafting by histologic and immunohistochemical examination of the grafts. Host reactivity to donor alloantigens was determined by assaying splenic T-cell proliferation and T-cell infiltration within the grafts, immunoglobulin-G subclass alloantibody levels (by flow cytometry), and cytokine production (by enzyme-linked immunosorbent assay or graft immunohistochemistry). Sixty days posttransplant, BALB/c allografts in wild-type B6 recipients showed severe chronic arteriopathy (intimal thickening, alpha-smooth muscle actin+ cell proliferation, fibrosis, and elastic lamina disruption). In contrast, profound deficiency of host myeloid, "lymphoid-related," and pre-plasmacytoid DC subsets was accompanied by marked reductions in each feature of chronic rejection. Improvement in graft appearance was associated with antigen-specific suppression of ex vivo anti-donor T-cell proliferative activity and reductions in interferon-gamma but with enhancement of interleukin-10 secretion in response to donor alloantigen challenge. Permanent deficiency of host DC subsets resulting from targeted gene disruption markedly inhibits the development of transplant vascular sclerosis, associated with striking reductions in both anti-donor T-cell reactivity and immunoglobulin-G alloantibody production.

Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia.

Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.

Expression of growth arrest-specific gene 6 and its receptors in a rat model of chronic renal transplant rejection.

Growth arrest-specific gene 6 (Gas6) is involved in a number of cell functions that include proliferation of vascular smooth muscle cells and mesangial cells. The proliferation of these cells is a feature of chronic rejection (CR) after kidney transplantation. Therefore, we examined the gene expression of Gas6 and its receptors Rse, Axl, and Mer in a rat model of CR. The rat model of CR was established in Lewis rat recipients of Fisher kidney transplants. The level of mRNA was measured by real-time quantitative reverse transcription-polymerase chain reaction. The proteins were detected by immunohistochemical staining and Western blot analysis. Gas6 mRNA was extensively expressed in kidney tissue of both allografts and isografts. There was significant increase in expression of Gas6 mRNA in allografts at 4 weeks posttransplantation. Immunohistochemical study showed that Gas6 and its receptor Rse proteins were highly expressed in kidney tissue. Western blot analysis has also confirmed that Gas6 and Rse proteins are expressed in kidney tissue. These findings suggest that Gas6 and its receptors have an as yet undefined role in kidney function and/or development and may be involved in the pathogenesis of CR. The action of Gas6 in rat kidney is mainly mediated through the Rse receptors rather than the Axl and Mer receptors.

Role of cytomegalovirus infection in transplant arteriosclerosis and chronic rejection

Chronic rejection is a serious limitation to long-term survival of all solid-organ allografts. The common pathologic feature of chronic rejection seen across all allografts is transplant arteriosclerosis (TA), an obliterative and fibrotic process involving the vasculature and other hollow structures. These changes are most apparent in cardiothoracic organ transplants, in which the majority of grafts are lost as a result of TA affecting the coronary artery disease after heart transplantation, and obliterative bronchiolitis (OB) after lung transplantation. Recently, considerable evidence has emerged supporting an important role for microorganisms in the disease process of vascular injury leading to chronic rejection. This evidence is based on epidemiologic and observational data from transplant recipients, as well as native organs, experimental models, and therapeutic trials. The organisms that have been implicated in the pathophysiology of arteriosclerosis, include Helicobacter pylori , chlamydia, and herpes viruses, most notably, cytomegalovirus (CMV). CMV infection has been reported as a risk factor for TA and OB, and patients who develop CMV disease after heart transplantation have been shown to have a higher incidence of TA and death from TA compared with those who remain free from the disease. Endomyocardial biopsies from patients during CMV viremia show endothelial and vascular smooth muscle cell proliferation, as well as endothelialitis, independent of acute rejection. These changes, which are consistent with vascular injury induced by CMV, have been shown to be markers of subsequent diffuse TA. Rodent models of heterotopic heart transplantation infected with rat CMV develop TA at an accelerated rate, and this process is partially inhibited by early, prophylactic treatment with the antiviral drug, ganciclovir. Similarly, patients treated prophylactically with ganciclovir during the initial 28 days after heart transplantation had a lower incidence of TA compared with placebo. However, this benefit was not seen in seronegative patients receiving hearts from seropositive donors, consistent with the high-risk nature of this group (D+/R−) for developing acute CMV disease. Recent studies have addressed the question of whether improved prophylaxis could be achieved with the addition of CMV hyperimmune globulin (CMVIG) in high-risk patients, including all donor or recipient seropositivity at lung transplantation. Using historical controls, these studies suggest that a combined regimen of ganciclovir plus CMVIG reduces the incidence of acute CMV disease, TA, OB, and death from OB. These observations emphasize the need for future, randomized, controlled trials to confirm a causal role for CMV (and other pathogens) in the disease process of TA and chronic rejection.

EGF and TGF-beta1 gene expression in chronically rejecting small bowel transplants.

Long-term survival of small bowel transplants is hampered by chronic rejection. Epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta) have opposing, regulatory roles in normal intestinal physiology and may be involved in the pathogenesis of chronic intestinal rejection. Our aim was to investigate the expression of EGF and TGF-beta1 in chronically rejecting small bowel transplants. Orthotopic small bowel transplantation was performed in the allogeneic DA-to-AS rat combination; Cyclosporin was administered temporarily to prevent acute rejection. Controls were DA isografts and normal DA rats. PreproEGF and TGF-beta1 gene expression was evaluated by northern blot analysis of the ileum RNA and standardized against glyceraldehyde-3-phosphate-dehydrogenase expression. Allografts demonstrated functional impairment and histological features of chronic rejection, whereas isografts appeared normal. Allografts demonstrated a significant reduction of EGF mRNA when compared to DA isografts. No significant changes were detected in TGF-beta1 expression in either allogeneic or syngeneic grafts. In conclusion, this study demonstrates reduced preproEGF and preserved TGF-beta1 gene expression in chronically rejecting small bowel transplants.

Rejection in organ transplantation.

Kidney transplantation has been established as a suitable alternative therapy to hemodialysis. Several new immunosuppressive agents contributed to the remarkable improvements in short-term graft survival. However, the rate of graft attrition over the long term has remained constant despite improvements in early success of transplantation during recent years. The half-life of cadaver kidneys, for instance, has consistently remained at 6-7 years throughout the entire transplant experience. Although chronic rejection is the major cause of organ graft loss over the long term, its etiology is not well defined and the pathophysiology of the process is not well understood. Isografts showing similar features of chronic rejection including functional deterioration and morphological changes, demonstrate that antigen-independent factors may also be important in the development of chronic rejection, as well as antigen-dependent factors.

Morphometric analysis of neointimal formation in murine cardiac grafts: III. Dissociation of intestitial fibrosis from neointimal formation.

This study examined the relationship between transplant vascular sclerosis (TVS) and tissue fibrosis, features of chronic rejection that can develop rapidly in accepted heterotopic murine cardiac allografts. The rate of development of interstitial fibrosis or TVS development was determined by computerized analysis of tissue sections from DBA/2-->C57BL/6 heterotopic cardiac allografts after immunosuppression with gallium nitrate. In accepted cardiac allografts, neointimal fibrosis developed by 30 days after transplant, whereas TVS was minimal by day 30, and maximal by day 60. Variable levels of fibrosis were found throughout the allografts. DBA/2-->DBA/2 cardiac isografts never displayed TVS in this time period, but displayed allograft-like fibrosis within 60 days of transplantation. Interstitial fibrosis can be dissociated from the TVS development in this experimental model of chronic cardiac allograft rejection. Apparently, it is caused, at least in part, by alloantigen-independent factors other than TVS-related tissue ischemia.

Successful treatment of ongoing intestinal allograft rejection permits recovery of graft structure and function

Acute rejection episodes often complicate clinical small bowel transplantation, which prompted us to investigate whether such episodes can be reversed and the intestinal graft salvaged. Inbred Lewis rats that received fully allogeneic Brown-Norway small bowel allografts were treated with cyclosporin A (10 mg/kg) for 5 days, and the drug was then discontinued. Clinical and histologic signs of acute rejection developed, and the animals were subsequently treated with FK 506 (2 mg/kg) on days 14, 16, and 18. Survival was significantly prolonged (201.7 +/- 46.8 days) when compared with animals that were not administered FK 506 (16.5 +/- 0.8 days) or allograft recipients that received no immunosuppressive therapy (10.8 +/- 0.7 days). The histologic changes and functional impairment due to rejection that were observed prior to the start of the FK 506-therapy were reversed. However, biopsy specimens of all animals exhibited features of chronic rejection. This study provides evidence that acute rejection of intestinal allografts can be successfully treated with a short course of FK 506.