Small bowel transplantation : immunological and functional studies

Small bowel transplantation (SBT) would be the treatment of choice for patients suffering from the short bowel syndrome. Although in some centers SBT in patients is done with a considerable degree of success (Grant et al 1990, Todo et al. 1992), it is by no means an established and widely applicable therapy for those with short bowel syndrome. The small bowel is unique among vascularized organ grafts because it not only elicits a vigorous rejection reaction, but is also capable of inducing graft-versus-host disease (GVHD). Rejection of the graft does not only lead to loss of function, but also to bacterial translocation. The risk of fatal sepsis is aggravated by the immunosuppression given to prevent rejection. This chapter describes the history of experimental and clinical SBT, and outlines recent developments and future prospects concerning this theoretically optimal treatment modality for patients who would be dependent on total parenteral nutrition (TPN) for life

The effect of immunosuppression on function of kidney allografts in the rat

Transplantation of living tissues is not a new concept. Greek mythology presents us with the Chimera in which a goat's body, a lion's head and a dragon's tail are joined to form a terrifying monster. Ancient Indian surgeons made use of local skin flaps for rhinoplasty, an art which has been practiced in Italy as early as the fifteenth century. Various transplantation experiments were performed by John Hunter in the eighteenth century. However, a systematic approach to the study of transplantation biology has only been started during the present century when technical progress in the field of surgery (Carrel and Guthrie 1905, 1906; Carrel 1908) made it possible to transplant a large variety of tissues and organs. Unfortunately, surgical problems are not the only obstacles to successful transplantation. lt has been known for a long time that tissue transplants in which the donor is also the recipient (autografts) or transplants between animals of the same inbred strain (isografts) will survive. Without complications this also applies to grafts between identical twins. On the other hand, transplants between two randomly chosen individuals of the same species called homografts or allografts, behave like autografts for a few days only, after which progressive damage occurs, leading to loss of function and destruction of the graft. This process, called rejection, is usually complete within a few weeks following transplantation and is invariably accompanied by infiltration with inflammatory cells, predominantly of the mononuclear type. In transplants exchanged between members of different species (heterografts, syn. xenografts), a much more violent and rapid rejection may take place

Small bowel transplantation: An overview

Small bowel transplantation (SBT) would, in theory, be the treatment of choice for patients suffering from the short bowel syndrome. Although SBT has been done with a considerable degree of success in some centers [36,145], it is by no means an established or widely applicable therapy for those with short bowel syndrome. The small bowel is unique among vascularized organ grafts because it not only elicits a vigorous rejection reaction but is also capable of inducing graft-versus-host disease (GVHD). Rejection of the graft does not only lead to loss of function but also to bacterial translocation. The risk of fatal sepsis is aggravated by the immunosuppression given to prevent rejection. Here, the history of SBT is described, and recent developments in experimental and clinical SBT, as well as future prospects for this theoretically optimal treatment modality for patients dependent on total parenteral nutrition (TPN) for life, are outlined

Dietary restriction and fasting arrest B and T cell development and increase mature B and T cell numbers in bone marrow

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many "neuronal and surgery related damaging phenomena" such as Parkinson's disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its antiinflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3+ T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

Background: Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue. Experimental approach: Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses. Key results: The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals. Conclusions: Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients

Disruption of clock gene expression in human colorectal liver metastases

The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis

Mannan-binding lectin is involved in the protection against renal ischemia/ reperfusion injury by dietary restriction

Preoperative fasting and dietary restriction offer robust protection against renal ischemia/ reperfusion injury (I/RI) in mice.We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake) or three days of water only fasting on MBL in 10-12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different. Copyright