UZ Leuven

Early presence of regulatory cells in transplanted rats rendered tolerant by donor-specific blood transfusion. Kitade H, Kawai M, Rutgeerts O, Landuyt W, Waer M, Mathieu C, Pirenne J.J Immunol 2005;175:4963-4970. Abstract: Mechanisms by which donor-specific blood transfusion (DSBT) promotes organ allograft acceptance are unclear. In a rat fully mismatched cardiac allograft model, we found that DSBT alone (without immunotherapy) induces the development of regulatory T cells (DSBT-Tregs) posttransplant, thereby shedding new light in the mechanisms of the transfusion effect. Compartments and timing of expansion, requirements, and phenotype of DSBT-Tregs are unknown. It is generally assumed that some time is necessary before Tregs develop. However, we show-by adoptive transfer from DSBT-tolerant into naive recipients: 1) the presence of DSBT-Tregs at 5 days posttransplant in spleen and lymph nodes; 2) their gradual expansion in these compartments; and 3) their presence in the graft 14 of 30 days posttransplant. DSBT-Tregs are donor specific and do not protect third-party allografts. Splenocytes from DSBT-treated nontransplanted recipients or from transplanted DSBT-untreated (rejecting) recipients do not transfer tolerance, indicating that both DSBT and graft are required for sufficient numbers of DSBT-Tregs to develop. Thymectomy (or splenectomy) before DSBT (not at transplantation) abrogate DSBT-Tregs generation and tolerance, showing that thymus (and spleen) are required for DSBT-Tregs generation (not for expansion/maintenance). In contrast with other Tregs models, DSBT-Tregs activity is not restricted to CD4(+)CD25(+) but to CD4(+)CD45RC(-) cells, whereas CD4(+)CD45RC(+) cells act as effector cells and accelerate rejection. In conclusion, DSBT alone induces-rapidly posttransplant-the development of alloantigen-specific Tregs in lymphoid tissues and in the graft. DSBT, graft, thymus, and spleen are required for DSBT-Tregs generation. DSBT-Tregs in this model are CD4(+)CD45RC(-) (identical to Tregs protecting from autoimmunity in rats).

Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo. Kawai M, Kitade H, Mathieu C, Waer M, Pirenne J.Transplantation 2005;79:1073-1077. Abstract: BACKGROUND: Regulatory T cells (Tregs) are increasingly recognized as playing a major role in nondeletional tolerance. To avoid rejection before tolerance is established, clinical trials of tolerance induction include immunosuppressive drugs early posttransplant. It is therefore essential that immunosuppressive protocols do not block Tregs generation. Tregs function has been shown to depend upon interleukin-2 signaling, but there are limited data available on how calcineurin inhibitors influence Tregs development and function in vivo. METHODS: To study this, we used a previously established rat cardiac allograft model where donor-specific Tregs and tolerance are induced by pretransplant donor-specific blood transfusion (DSBT). RESULTS: In this model, we found that adjunction of 50 mg/kg cyclosporine (CsA) (not a lower dose, 10 mg/kg) at the time of DSBT (not at the time of transplantation) abrogates Tregs development and causes rejection. Interestingly, 10 mg/kg CsA given posttransplant (day 0-11) in the absence of pretransplant DSBT induced the development of Tregs and provoked a state of tolerance indistinguishable from the one induced by DSBT. Finally, DSBT given the day of transplantation did not promote tolerance, unless recipients also received a delayed short course (day 5-9) of 10 mg/kg CsA. CONCLUSIONS: Adjunction of high-dose CsA to pretransplant DSBT abrogates Tregs generation. On the contrary, a lower dose (10 mg/kg) of CsA promotes Tregs development either in synergy with perioperative DSBT (providing that a drug-free interval is respected) or by its own effect. These data provide new guidelines for a more tolerogenic use of calcineurin inhibitors in the clinic, particularly when immunomodulatory strategies aimed at inducing Tregs are applied.

Combined “en bloc” liver and pancreas transplantation in patients with liver disease and type 1 diabetes mellitus. Pirenne J, Deloose K, Coosemans W, Aerts R, Van Gelder F, Kuypers D, Maes B, Verslype C, Yap P, Van Steenbergen W, Roskams T, Mathieu C, Fevery J, Nevens F. Am J Transplant 2004;4:1921-1927. Abstract: Liver disease alters the glucose metabolism and may cause diabetes, but this condition is potentially reversible with liver transplantation (LTx). Type 1 diabetes mellitus may be coincidentally present in a LTx candidate and immunosuppressive drugs will aggravate diabetes and make its management more difficult for posttransplant. In addition, diabetes negatively influences outcome after LTx. Therefore, the question arises as to why not transplanting the pancreas in addition to the liver in selected patients suffering from both liver disease and Type 1 diabetes. We report two cases of en bloc combined liver and pancreatic transplantation, a technique originally described a decade ago in the treatment of upper abdominal malignancies but rarely used for the treatment of combined liver disease and Type 1 diabetes. Both recipients are currently liver disease-free and insulin-free more than 2 and 4 years posttransplant, respectively. Surgical, medical and immunological aspects of combined liver-pancreas transplantation are discussed in the light of the existing relevant literature.

Tolerance of liver transplant patients to strenuous physical activity in high-altitude. Pirenne J Van Gelder F, Kharkevitch T, Nevens F, Verslype C, Peetermans WE, Kitade H, Vanhees L, Devos Y, Hauser M, Hamoir E, Noizat-Pirenne F, Pirotte B.Am J Transplant 2004;4:554-560. Abstract: Physical functioning is improved after liver transplantation but studies comparing liver transplant recipients with normal healthy people are lacking. How liver (and other organ) transplant recipients tolerate strenuous physical activities is unknown. There are no data on the tolerance of transplant patients at high altitude. Six liver transplant subjects were selected to participate in a trek up Mount Kilimanjaro 5895 m, Tanzania. Physical performance and susceptibility to acute mountain sickness were prospectively compared with fifteen control subjects with similar profiles and matched for age and body mass index. The Borg-scale (a rating of perceived exertion) and cardiopulmonary parameters at rest were prospectively compared with six control subjects also matched for gender and VO2max. Immunosuppression in transplant subjects was based on tacrolimus. No difference was seen in physical performance, Borg-scales and acute mountain sickness scores between transplant and control subjects. Eight-three percent of transplant subjects and 84.6% of control subjects reached the summit (p=0.7). Oxygen saturation decreased whereas arterial blood pressure and heart rate increased with altitude in both groups. The only difference was the development of arterial hypertension in transplant subjects at 3950 m (p=0.036). Selected and well-prepared liver transplant recipients can perform strenuous physical activities and tolerate exposure to high altitude similar to normal healthy people.

Livers from non-heart-beating donors tolerate short periods of warm ischemia. Monbaliu D, Crabbé T, Roskams T, Fevery J, Verwaest C, Pirenne J.Transplantation 2005;79:1226-1230.
Abstract: BACKGROUND: In contrast with kidneys, transplantation of livers originating from non-heart-beating donors remains rare, mainly because warm ischemia causes a higher rate of potentially lethal primary graft nonfunction. Little is known on the tolerance of liver grafts to warm ischemia. No techniques are available to assess the viability of ischemic livers before implantation. Therefore, experimental models are needed to address these questions before non-heart-beating liver transplantation can be more widely applied. This study aims to develop a reproducible large animal model of liver transplantation using non-heart-beating donors and, in this model, to define the tolerance of the liver to warm ischemia. METHODS: Pigs weighing 25to 30 kg are used. In donors, cardiac arrest is caused by ventricular fibrillation. After increasing lengths of warm ischemia (0, 15, 30, 45, and 60 min), the liver is flushed in situ with 4 degrees C histidine tryptophan ketoglutarate preservation solution and procured. The liver is transplanted after a 4-hour cold storage period. RESULTS: Control livers (no warm ischemia) and livers exposed to 15 minutes of warm ischemia function normally after transplantation, whereas all livers submitted to 60 minutes of warm ischemia display primary nonfunction and cause recipient death. Graft function and survival are occasionally observed after 30 and 45 minutes of warm ischemia. CONCLUSIONS: A reproducible model of non-heart-beating liver transplantation is described. We found that the liver tolerates 15 minutes of warm ischemia. This preclinical model is a valid tool to develop techniques to predict the quality of ischemic livers before implantation and to design interventional strategies to improve the tolerance of the liver to warm ischemia.

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