Effect of dietary fish oil supplementation on eicosanoid production by rat renal allografts

Acute renal allograft rejection is associated with significant alterations in renal arachidonic acid (AA) metabolism including increased production of the vasoconstrictor eicosanoid thromboxane (TX)A2. TX synthetase inhibition improves function of rejecting rat renal allografts but is difficult to accomplish pharmacologically. Therefore, we evaluated the potential use of dietary fish oil (FO) as a more practical method for reducing renal thromboxane production. We examined the effects of dietary FO supplementation on eicosanoid production and hemodynamic function of rat renal allografts. Donor and recipient rats were fed a fat-free diet supplemented with beef tallow (BT) or FO. After 6 weeks on the experimental diet, kidneys from ACI donors were transplanted into PVG recipients. Six days after transplant, renal function and eicosanoid production were measured. FO feeding resulted in significant alterations in eicosanoid production by renal allografts. There was a marked and generalized reduction in prostaglandin (PG) and TX production by allografts when both donor and recipient were fed a diet supplemented with fish oil. An intermediate reduction in production of PGE2 (and perhaps PGI2), but not TXB2, was observed when only the recipient was fed FO. Feeding FO to the donor alone had no effect on renal PG or TX production. These data suggest that both donor and recipient fatty acid pools contribute to AA metabolism during rejection. Unlike specific TX inhibition, the generalized inhibition of AA metabolism that occurred with FO feeding was not associated with improvement in function or morphology of allografts. However, potential benefit at earlier stages or in milder forms of rejection is possible and was not evaluated.     

Fatty acid intake and Kupffer cell function: fish oil alters eicosanoid and monokine production to endotoxin stimulation

Diets high in n-3 fatty acids appear to have an anti-inflammatory effect, which is thought to be due to decreased macrophage prostaglandin (PG) and thromboxane (Tx) production after incorporation of these fatty acids into cell membrane phospholipids. The effect of n-3 fatty acids incorporation on macrophage monokine release in response to septic stimuli is not well established. Kupffer cells, the fixed macrophages of the liver, were obtained from rats fed diets with fat sources derived from corn oil (CO, control), fish oil (FO, high in n-3 fatty acids), or safflower oil (SO, high in n-6 fatty acids) for 2 or 6 weeks. After exposure to bacterial lipopolysaccharide, Kupffer cells from rats fed FO for 2 or 6 weeks produced less PG and Tx than Kupffer cells from rats fed CO or SO. After 2 weeks of defined diets, interleukin-1 (IL-1) and tumor necrosis factor release were not affected by dietary fat source. In contrast, after 6 weeks of feeding, Kupffer cells from both the FO and the SO groups released less IL-1 and tumor necrosis factor when triggered by lipopolysaccharide than Kupffer's cells from animals fed the control diet that contained CO. These data suggest that altered monokine release from macrophages may contribute to the anti-inflammatory effect of diets high in n-3 fatty acids. Also shown in our results is that prolonged changes in membrane phospholipid content induced by dietary fat source can influence not only PG and Tx production but monokine release as well.     

The effect of donor specific transfusions and dietary fatty acids on rat cardiac allograft survival

A rat heterotopic cardiac transplant model was used to study the effect of dietary lipids on the immune response. Animals receiving linoleic acid (LA), oleic acid (OA), and fish oil (FO) enriched diets showed significant prolongation of allograft survival when compared to the control diet fed animals. When LA was given to animals who had received a single donor specific transfusion (DST) augmentation of the beneficial DST effect was observed, while the OA and FO fed groups showed no differences from control DST animals. Dietary regulation of the immune response, possibly through manipulation of arachidonic acid metabolism, is implied.     

Lipid mediated modification of rat heart allograft survival

The effect on allograft survival of intravenous fat emulsions that differed in the ratio of functionally important n-3 and n-6 fatty acids was studied in a heterotopic cardiac transplant model in rats. Twenty percent fat emulsions were administered by continuous infusion at a dosage of 9 g fat/kg body weight per day, starting immediately after transplantation and continuing until complete rejection. The n-6 and n-3 fatty acids represent 75%, 43%, 60%, and 59% of all fatty acids in safflower oil, fish oil, soybean oil, and a 1:1 mixture of safflower and fish oil, respectively. The n-6 fatty acids predominate in safflower oil (370/1) and soybean oil (6.5/1), while the n-3 fatty acids dominate in the fish oil (7.6/1). The 1:1 mixture of safflower and fish oil has the balanced composition (n-6/n-3=2.1/1) recommended by Kinsella and served as oil-treated controls. Continuous infusion of safflower oil, fish oil, and soybean oil prolonged graft survival time to 13.3, 12.3, and 10.4 days, respectively, compared to 6.8 days in the oil-treated controls (P<0.01 for all comparisons). Another control group infused with saline rejected the allografts after 7.8 days (P=NS compared to oil-treated controls; P<0.01 for all other comparisons). The data suggest that intravenous administration of polyunsaturated fat emulsions results in an immunosuppressive effect that seems to be dependent on the n-3/n-6 fatty acid ratio of the fat emulsion. The n-6 fatty acids turned out to be just as immunosuppressive as the n-3 fatty acids if each fatty acid family was applied as the main polyunsaturated fatty acid source. Soybean oil with a n-3/n-6 fatty acid ratio, coming closer to the ratio of the oil-treated controls, was significantly less immunosuppressive than safflower oil.     

Fatty acid composition and arachidonic acid concentrations in alveolar bone of rats fed diets with different lipids

Summary The purpose of the present study was to determine if the type of dietary fat can modify the fatty acid composition and arachidonic acid levels in the alveolar bone phospholipids. Three groups of rats were fed nutritionally adequate semipurified diets containing different lipids: 10% corn oil (control, group 1, rich in n-6 fatty acids); 9% butter + 1% corn oil (experimental, group 11, rich in saturated fatty acids); and 9% ethyl ester concentrate of n-3 fatty acids + 1% corn oil (experimental, group 111, rich in n-3 fatty acids). After 10 weeks of feeding the various diets, rats were killed, maxillae and mandibles were dissected out, and the soft tissue was removed. Bone was frozen in liquid nitrogen and pulverized. Powdered bone was extracted for total lipids, and phospholipids were isolated by column chromatography. The fatty acid composition and arachidonic acid concentrations were determined in total phospholipids after the addition of an internal standard, octadecatetraenoic acid (18: 4n-3), and subsequent gas chromatography. The type of dietary lipids had a profound influence on the fatty acid composition of bone lipids. Arachidonic acid concentrations were significantly lower in total phospholipids of mandibles and maxillae of rats fed the experimental diets than in those fed the control diet. Because arachidonic acid is a precursor of prostaglandin E₂ and leukotriene C₄, a significant reduction in its concentration may result in reduced levels of these eicosanoids in the alveolar bone.Presented in part at the International Association for Dental Research Meeting, Glasgow, Scotland, July 1–4, 1992     

High linoleic acid diets ameliorate diabetic nephropathy in rats

The value of high polyunsaturated fatty acid (PUFA) diets in preventing diabetic nephropathy in rats was studied. Diabetes was induced by intravenous injection of streptozotocin (SZ), 65 mg/kg. Rats were divided in four groups fed diets containing 11% fat for 38 weeks. Dietary fat derived from four sources: beef tallow (BT; rich in saturated fatty acids), evening primrose oil (EPO; rich in gamma linolenic [GLA] and linoleic acids [LA]), safflower oil (SO; rich in LA), and fish oil (FO; rich in eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids). Ultralente insulin was administered every other day to maintain the blood glucose levels between 11.1 and 22.2 mmol/L (200 and 400 mg/dL). The diets prepared with EPO and SO had a clear beneficial effect on proteinuria, glomerular sclerosis, and tubular abnormalities, as compared with BT. Both diets also increased the ratio of renal cortical production of 6-keto-PGF1 alpha to thromboxane B2 (TXB2), the stable metabolites of PGI2 and TXA2, respectively. They did not induce significant changes in plasma lipid composition. The FO diet did not have an effect on renal disease, but decreased plasma lipids and inhibited eicosanoid synthesis by platelets and kidney cortex. FO feeding was associated with a lowered 6-keto-PGF1 alpha/TXB2 ratio. It is concluded that high LA diets are protective in this model of diabetic nephropathy. The effect may be secondary to modifications of the eicosanoid balance. Diets containing FO have a beneficial effect on plasma lipids in this model.     

Prevention of bronchiolitis obliterans in rat lung allografts by type V collagen-induced oral tolerance

BACKGROUND: We have reported that feeding type V collagen (col(V)) to lung allograft recipients induces immune tolerance that prevents acute lung allograft rejection. Repeated acute rejection is a risk factor for or associated with chronic rejection, known as bronchiolitis obliterans (BO), the leading cause of death in lung allograft recipients. The current study examines if col(V)-induced oral tolerance prevents BO. METHODS: WKY rats (RT1l) were fed either col(V) or diluent before orthotopic transplantation of F344 (RT1lvl) lung allografts. No rats received any immunosuppression. At 10 weeks posttransplantation the time to onset of BO, delayed type hypersensitivity (DTH) responses to donor antigens, and col(V) were examined. In addition, proliferative responses of recipient T lymphocytes to donor antigens, and ability of recipient antigen presenting cells to present alloantigens in lung allografts were evaluated. RESULTS: The data show that recipient rats have sustained DTH responses to donor antigens and col(V). T lymphocytes from col(V)-fed lung allograft recipients were unable to proliferate in response to donor antigens, but feeding col(V) had no effect on the presentation of donor alloantigens by recipient antigen presenting cells. All diluent fed rats developed BO, but only mild acute rejection (grade 2) was present in all rats fed col(V). Transforming growth factor (TGF)-beta production was up-regulated systemically in col(V)-fed, but not diluent fed, lung allograft recipients, and neutralizing TGF-beta [corrected] recovered the DTH response to donor antigens in col(V)-fed rats. CONCLUSIONS: Collectively these data show that col(V)-induces oral tolerance that prevents BO, and that tolerance may be mediated by systemic production of TGF-beta [corrected].     

Consumption of different sources of omega-3 polyunsaturated fatty acids by growing female rats affects long bone mass and microarchitecture

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) consumption has been reported to improve bone health. However, sources of ω-3 PUFAs differ in the type of fatty acids and structural form. The study objective was to determine the effect of various ω-3 PUFAs sources on bone during growth. Young (age 28d) female Sprague-Dawley rats were randomly assigned (n=10/group) to a high fat 12% (wt) diet consisting of either corn oil (CO) or ω-3 PUFA rich, flaxseed (FO), krill (KO), menhaden (MO), salmon (SO) or tuna (TO) for 8 weeks. Bone mass was assessed by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture by micro-computed tomography (μCT). Bone turnover markers were measured by enzyme immunoassay. Lipid peroxidation was measured by calorimetric assays. Results showed that rats fed TO, rich in docosahexaenoic acid (DHA, 22:6ω-3) had higher (P<0.009) tibial bone mineral density (BMD) and bone mineral content (BMC) and lower (P=0.05) lipid peroxidation compared to the CO-fed rats. Reduced lipid peroxidation was associated with increased tibial BMD (r2=0.08, P=0.02) and BMC (r2=0.71, P=0.01). On the other hand, rats fed FO or MO, rich in alpha-linolenic acid (ALA, 18:3ω-3), improved bone microarchitecture compared to rats fed CO or SO. Serum osteocalcin was higher (P=0.03) in rats fed FO compared to rats fed SO. Serum osteocalcin was associated with improved trabecular bone microarchitecture. The animal study results suggest consuming a variety of ω-3 PUFA sources to promote bone health during the growth stage.     

Effects of dietary protein restriction and oil type on the early progression of murine polycystic kidney disease.

A paucity of research data exists on the potential for early dietary modification to directly retard cystic growth and proliferation in polycystic kidney disease (PKD). We have therefore examined the relative effects of dietary protein levels and oil type on the progression of disease in a murine model of PKD. In the first study, weanling DBA/2FG-pcy (pcy) mice were fed either a normal (NP), 25%, or low (LP), 6%, casein diet with 10% of either sunflower seed oil (SO) (containing n-6 fatty acids), or fish oil (FO) (containing n-3 fatty acids), in a 2 x 2 design. At the end of the dietary treatment, kidney weight relative to body weight was higher in mice on the NP diets. In addition, kidney phospholipid to kidney weight (mumol/g) was lower in pcy mice on NP diets, indicating that the increased kidney size was largely due to increased cyst development. Replacement of dietary SO with FO resulted in alterations in renal phospholipid fatty acid compositions: 18:2 n-6, 20:4 n-6, and 22:5 n-6 were lower, and 20:5 n-3, 22:5 n-3, and 22:6 n-3 were higher in FO-fed animals. No effect of dietary lipid type on disease progression was noted, however. In a second study, morphometric analysis revealed an 11% lower percentage cyst area and a 46% lower total cyst area (mm2) in kidney sections derived from mice on LP diets compared to NP diets. These results indicate that early dietary protein restriction in PKD prior to clinical manifestation of symptoms of the disease may have a significant impact on the pathogenesis of PKD.     

Inhibition of warm ischemic injury to rat liver, pancreas, and heart grafts by controlling the nutritional status of both donor and recipient

In this study, we tested the effect of donor fasting with or without the use of an essential fatty acids deficiency (EFAD) diet in the recipient using rat heart, pancreas, and liver transplant models. We then compared the survivals, tumor necrosis factor alpha (TNF-α) response, and white cell accumulation in rats in order to clarify the mechanisms of the beneficial effect of donor fasting and recipient EFAD. It was found that when the grafts were obtained from fasted donors and then transplanted into fed recipients, the survival rate was significantly higher for all three grafts than for those obtained from fed rats and transplanted into fed rats. The best survival was seen for pancreas grafts obtained from fasted donors and then transplanted into EFAD recipients. TNF-α secretion was significantly suppressed in both fasted and EFAD rats, and both the total cell count and neutrophil count were suppressed in EFAD rats. These results clearly indicate that in addition to liver grafts, both heart and pancreas grafts obtained from fasted animals are more tolerant to warm ischemic injury. Furthermore, the combination of donor fasting and recipient EFAD acts synergistically to inhibit the post-transplantation inflammatory reaction (through decreased TNF-α secretion and white cell accumulation), thus resulting in an improved survival.     

Effect of stress and dietary fatty acids on allograft survival in the rat.

To determine the immunosuppressive effect of stress and a diet rich on linoleic acid on vascularized organ graft survival in the rat, a series of allogeneic heart and kidney grafts were carried out. Restraint stress resulted in a significant prolongation of the survival time. Although 5 days of postoperative stress gave the best results, 3 h of stress given on the first postoperative day already gave a marked prolongation of the survival time of kidney allografts. The beneficial effect of stress on heart survival was abolished when prior adrenalectomy was carried out. A diet high on polyunsaturated fatty acids gave significant prolongation of the survival times of kidney-grafted rats. A diet hgh on saturated fatty acids did not result in a statistical significant prolongation of the survival time, although the difference with the polyunsaturated fatty acid group was very small and not statistically significant. It was concluded that stress and diets high in certain types of fatty acids depress the immune response in rats, possibly via a mechanism which has some common pathways. The adrenal glands could play an important role in this immune inhibition.     

Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats

We previously reported that renal injury in hyperlipidemic, obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA, fish oil rich in n-3 PUFA, coconut oil medium-chain saturated fatty acid, or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria, mesangial matrix expansion, and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides, and improved the composition of triglyceride-enriched lipoproteins, only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general, the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA, either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked, and that dietary supplementation with PUFA may ameliorate chronic, progressive renal injury.     

Prolonged survival of rat cardiac allografts by donor pretreatment with methotrexate. Enhancement by combined immunosuppressant treatment of the recipient

Using an intraabdominal heterotopic cardiac transplant procedure, we determined that the Fischer 344 rat (donor)/Long Evans rat (recipient) combination provides a suitable model for studying acute rejection of cardiac allografts. Rejection time was 9.7 +/- 0.2 days. With this model we investigated the effect of donor pretreatment with methotrexate on allograft survival. Methotrexate injection at a single optimum dose of 100-200 mg/kg, i.p., resulted in a 55-60% increase in allograft survival with indefinite survival of some allografts. The optimum time for methotrexate administration was found to be 3-24 hr before transplant, indicating the clinical feasibility of this approach. Combining methotrexate with different recipient treatments (cyclosporine, methylprednisolone, or methylprednisolone plus azathioprine) resulted in significantly longer allograft survival than with any treatment alone. We have demonstrated a novel and clinically feasible approach to the treatment or prevention of acute allograft rejection. Such a treatment could allow reduction in the dose of immunosuppressant drugs to the recipient and thus lessen the toxicity of immunosuppressant therapy.     

Elevated bone turnover in rat polycystic kidney disease is not due to prostaglandin E2

Hyperparathyroidism, secondary to renal disease, is thought to cause high bone turnover via prostaglandin E2 (PGE2). Diets high in n-3 fatty acids reduced PGE2. Thus the objective was to compare the effect of diets high in n-6 and n-3 fatty acids on hyperparathyroidism, bone turnover, and PGE2 in Han:SPRD- cy rats that develop polycystic kidney disease (PKD). Weanling male rats ( n=58) were randomized to diets made with either corn or flaxseed oil (5%) for 8 weeks, followed by measurement of plasma parathyroid hormone (PTH), osteocalcin, urinary N-telopeptide (NTX), and ex vivo release of PGE2from femur. Plasma PTH was elevated ( P<0.01) as a result of PKD. Mean values for plasma osteocalcin and urinary NTX were elevated ( P<0.01) by PKD but not altered by diet. In contrast, values for PGE2 were lowest in the PKD rats fed flaxseed oil compared with PKD rats fed corn oil and compared with non-affected rats fed either oil. Rats with PKD have high-turnover bone disease, likely due to hyperparathyroidism, that is unaffected by feeding corn or flaxseed oils. Since PGE2 release is lower in the presence of high bone turnover, the high bone turnover in evolving rat uremia is not likely to be mediated by PGE2.     

Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice.

The mechanisms of action of dietary fish oil (FO) on osteoporosis are not fully understood. This study showed FO decreased bone loss in ovariectomized mice because of inhibition of osteoclastogenesis. This finding supports a beneficial effect of FO on the attenuation of osteoporosis. INTRODUCTION: Consumption of fish or n-3 fatty acids protects against cardiovascular and autoimmune disorders. Beneficial effects on bone mineral density have also been reported in rats and humans, but the precise mechanisms involved have not been described. METHODS: Sham and ovariectomized (OVX) mice were fed diets containing either 5% corn oil (CO) or 5% fish oil (FO). Bone mineral density was analyzed by DXA. The serum lipid profile was analyzed by gas chromatography. Receptor activator of NF-kappaB ligand (RANKL) expression and cytokine production in activated T-cells were analyzed by flow cytometry and ELISA, respectively. Osteoclasts were generated by culturing bone marrow (BM) cells with 1,25(OH)2D3. NF-kappaB activation in BM macrophages was measured by an electrophoretic mobility shift assay. RESULTS AND CONCLUSION: Plasma lipid C16:1n6, C20:5n3, and C22:6n3 were significantly increased and C20:4n6 and C18:2n6 decreased in FO-fed mice. Significantly increased bone mineral density loss (20% in distal left femur and 22.6% in lumbar vertebrae) was observed in OVX mice fed CO, whereas FO-fed mice showed only 10% and no change, respectively. Bone mineral density loss was correlated with increased RANKL expression in activated CD4+ T-cells from CO-fed OVX mice, but there was no change in FO-fed mice. Selected n-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) added in vitro caused a significant decrease in TRACP activity and TRACP+ multinuclear cell formation from BM cells compared with selected n-6 fatty acids (linoleic acid [LA] and arachidonic acid [AA]). DHA and EPA also inhibited BM macrophage NF-kappaB activation induced by RANKL in vitro. TNF-alpha, interleukin (IL)-2, and interferon (IFN)-gamma concentrations from both sham and OVX FO-fed mice were decreased in the culture medium of splenocytes, and interleukin-6 was decreased in sham-operated FO-fed mice. In conclusion, inhibition of osteoclast generation and activation may be one of the mechanisms by which dietary n-3 fatty acids reduce bone loss in OVX mice.     

Ex vivo allotransplantation engineering: Delivery of mesenchymal stem cells prolongs rejection‐free allograft survival

Current pharmacologic regimens in transplantation prevent allograft rejection through systemic recipient immunosuppression but are associated with severe morbidity and mortality. The ultimate goal of transplantation is the prevention of allograft rejection while maintaining recipient immunocompetence. We hypothesized that allografts could be engineered ex vivo (after allotransplant procurement but before transplantation) by using mesenchymal stem cell–based therapy to generate localized immunomodulation without affecting systemic recipient immunocompetence. To this end, we evaluated the therapeutic efficacy of bone marrow–derived mesenchymal stem cells in vitro and activated them toward an immunomodulatory fate by priming in inflammatory or hypoxic microenvironments. Using an established rat hindlimb model for allotransplantation, we were able to significantly prolong rejection‐free allograft survival with a single perioperative ex vivo infusion of bone marrow–derived mesenchymal stem cells through the allograft vasculature, in the absence of long‐term pharmacologic immunosuppression. Critically, transplanted rats rejected a second, nonengineered skin graft from the same donor species to the contralateral limb at a later date, demonstrating that recipient systemic immunocompetence remained intact. This study represents a novel approach in transplant immunology and highlights the significant therapeutic opportunity of the ex vivo period in transplant engineering.     

Improvement of Bone Quality in Gonad-Intact Middle-Aged Male Rats by Long-Chain n-3 Polyunsaturated Fatty Acid

The effect of long-chain n-3 polyunsaturated fatty acid (PUFA) on bone measurements was evaluated in gonad-intact middle-aged male rats. Seven rats were killed on day 0 of dietary intervention to determine bone parameters at baseline. Experimental rats (7/group) were fed one of the following lipid treatments (g/kg diet): 167 g safflower oil + 33 g menhaden oil (N6+N3 diet, control), 200 g safflower oil (N6 diet), or 190 menhaden oil + 10 g corn oil (N3 diet). After 20 weeks of dietary treatment, all groups had lower values for peak load and ultimate stiffness in femurs compared to baseline values. Rats fed the N3 diet had the highest values for peak load, ultimate stiffness, and Young’s modulus compared with those fed the N6 and control diets. Compared to baseline, all dietary treatment groups had significantly lower values for trabecular thickness and number in proximal tibia but higher values for trabecular separation and formation rate in proximal tibia and endocortical bone formation rate in tibial shaft. Compared with the control group, rats fed the N3 diet had lower values for formation rate, osteoclast number, and eroded surface in proximal tibia but higher values for periosteal mineral apposition and formation rates in tibia shaft. These findings indicate that a diet rich in long-chain n-3 PUFA mitigate aging-induced loss of bone integrity in intact middle-aged male rats through reducing bone turnover rate by suppressing both bone formation and resorption as a result of a larger net bone volume and modulating endocortical and cancellous bone compartments. Previously presented in part at the 26 th annual meeting of the American Society of Bone and Mineral Research, Seattle, Washington, USA, September 2004, and published in abstract form (Shen CL, Dunn DM, Yeh JK [2005] Dietary fish oil mitigates aging-induced bone loss in middle-aged male rats [abstract]. J Bone Miner Res 19(suppl 1):S205).     

Prolongation of allograft survival by passenger donor regulatory T cells

Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact on host immunity is unclear. Here, we examine whether transferred donor natural regulatory CD4 T cells (nT‐regs) inhibit host alloimmunity and prolong allograft survival. Transfer of donor‐strain lymphocytes was first assessed by identifying circulating donor‐derived CD4 T cells in 21 consecutive human lung transplant recipients, with 3 patterns of chimerism apparent: transient, intermediate, and persistent (detectable for up to 6 weeks, 6 months, and beyond 1 year, respectively). The potential for transfer of donor nT‐regs was then confirmed by analysis of leukocyte filters recovered from ex vivo normothermic perfusion circuits of human kidneys retrieved for transplantation. Finally, in a murine model of cardiac allograft vasculopathy, depletion of donor CD4 nT‐regs before organ recovery resulted in markedly accelerated heart allograft rejection and augmented host effector antibody responses. Conversely, adoptive transfer or purified donor‐strain nT‐regs inhibited host humoral immunity and prolonged allograft survival, and more effectively so than following administration of recipient nT‐regs. In summary, following transplantation, passenger donor‐strain nT‐regs can inhibit host adaptive immune responses and prolong allograft survival. Isolated donor‐derived nT‐regs may hold potential as a cellular therapy to improve transplant outcomes.     

The transmission of donor-derived malignant melanoma to a renal allograft recipient

The transmission to organ transplant recipients of donor origin malignancy in the allograft has been described. Here we report the transmission of malignant melanoma in a renal allograft transplanted from a multiorgan donor. The lung transplant recipient presented with an allograft lesion that was proven to be melanoma and of donor-origin based on human leukocyte antigen (HLA)-DR typing. One renal allograft recipient was undergoing his second deceased donor renal transplant, having lost his first graft from recurrent IgA nephropathy. He was unsensitized and immunosuppression consisted of tacrolimus, mycophenolate and prednisolone. He achieved stable graft function and there were no episodes of rejection. Four and a half months post-transplant a diagnosis of donor origin melanoma in the lung recipient was made and his immunosuppression was stopped. He presented with clinical rejection two wk later and a transplant nephrectomy was undertaken. Histology demonstrated vascular and cellular rejection and there was a 3-mm melanoma deposit with no evidence of tumour infiltrating lymphocytes. Three years post-transplant he remained clinically well with no evidence of melanoma and received his third deceased donor renal transplant. This was complicated by cellular rejection in the first week treated with methylprednisolone and vascular rejection at day 10 treated with anti-thymocyte globulin. Three months post-transplant he has achieved good allograft function and remains well with no evidence clinically or on imaging of metastatic melanoma. The other renal allograft recipient was receiving his first deceased donor transplant, having end-stage renal failure of uncertain aetiology. His immunosuppression was not stopped until melanoma was proven in the renal allograft pair six months post-transplant and he then presented with clinical rejection six wk later. Transplant nephrectomy was undertaken and histology did not demonstrate melanoma, but severe vascular and cellular rejection was evident. At three-yr post-transplant he remains disease free clinically and on imaging. At present, the cardiac allograft recipient has no evidence of transmitted melanoma. The highest risk of transmission of donor origin melanoma appears to be from donors who are older and have died from an intracerebral haemorrhage. It is likely these donors have metastatic melanoma and their intracerebral haemorrhage is not primary but has occurred in an unrecognized metastatic cerebral deposit. While the occurrence of donor-transmitted malignancy is not common, the outcome is often fatal.