Biliary secretory IgA levels in rats with protein-calorie malnutrition.

Malnutrition is a recognized cause of failure of host defense mechanisms. In the past 5 years, it has been demonstrated that the gut, long known to have significant morphologic changes with protein calorie malnutrition (PCM), is an immune organ affected by malnutrition. To assess the role of biliary immunoglobulin A (S-IgA), part of the barrier to bacterial invasion from the gastrointestinal tract, the following study was performed. Seventy-eight Fisher female inbred rats weighing 110-130 g were randomly separated into two groups. The control rats were fed standard rat chow. The experimental rats were fed a 2% agar protein depletion (PCM) diet (USP XV). The biliary tract of the rat was cannulated with Silastic tubing and bile flow and rat secretory immunoglobulin A (S-IgA) was sampled at intervals. S-IgA was measured by the Elisa method. Total bile protein was measured by micro-Kjeldahl. Bile was collected from the rats on day 0, 7, 14, 21, 29, 36, 42, and 49. During the study, the weight of rats fed the PCM diet decreased from 127.4 +/- 14.5 g at day 0 to 83 +/- 2.6 g on day 37. Control rats gained weight from 124.4 +/- 14.5 g at day 0 to 153.6 +/- 3.8 g at day 37. Total biliary protein at day 0 was 2.52 +/- .05 mg/ml and at day 36 was 2.51 +/- 11 mg/ml for PCM rats and 2.57 +/- 10 mg/ml for control rats. Normal rats and control rats both had an initial increase of S-IgA from 2.74 +/- 73 mg/ml on day 0 to 5.75 +/- 1.75 mg/ml on day 37. Both PCM and control rats demonstrated an increase in S-IgA levels despite significant loss of weight in the experimental group. Similarly, total biliary protein was not decreased in either group. The results suggest that gut immune system is preserved despite significant protein calorie malnutrition.     

The assessment of protein-calorie malnutrition in patients with gastrointestinal cancer

Daily protein and calorie intake, three plasma protein estimations, two upper limb anthropometric measurements, and estimated weight loss were all determined in 31 patients attending a surgical oncology outpatient department. The patients, who had had prior resection of a gastrointestinal cancer, could be divided into three groups depending on (i) the absence of clinically detectable tumour; (ii) the presence of clinically detectable tumour with survival over the ensuing four-month period; and (iii) clinically detectable tumour without survival over the ensuing four-month period. The variables least able to discriminate between these groups, and to interrelate to the other variable in a cross-correlation matrix, were the dietary intake data and the estimated weight loss. It is concluded that protein-calorie malnutrition can be adequately assessed in patients with advanced cancer from studies of the plasma albumin, prealbumin, transferrin, arm fat area, and arm muscle area.     

An experimental study on cellular immunity and protein-calorie malnutrition

The effect on cellular immunity of the administration of the non-specific immunopotentiator BCG and/or a streptococcal agent was studied in 90 non-cancer bearing Wistar rats under different nutritional support. The number of immunocompetent cells and the non-specific function of the immunocompetent cells significantly decreased in acute malnutrition. The non-specific immunopotentiator BCG and streptococcal agent activated the peritoneal macrophages, to a remarkable extent, but depressed spleen cell blastoid transformation, thymus index and peripheral lymphocyte count in the starved rat group. In rats who received BCG under intravenous hyperalimentation (IVH), the absolute macrophage counts went down as the quantity of amino-acid administered decreased. The acquired immunodeficiency due to acute malnutrition is evident and the effect obtained with an immunopotentiator is considered to be related to the nutritional status of the host. The adequate administration of protein-calorie is required for the effective use of the immunopotentiator.     

Effects of protein-calorie malnutrition and refeeding on fluorouracil toxicity

Mice were used to study the effects of protein-calorie malnutrition and its reversal on granulocyte-macrophage production and fluorouracil's toxic effect on bone marrow. An in vitro quantitative clonal culture technique for bone marrow granulocyte-macrophage progenitor cells (GM-CFC) was used. Animals on a protein-free but otherwise complete diet for ten days had a significant contraction in total marrow cellularity and GM-CFC numbers paralleling the animal's weight loss. The acute toxic effect of fluorouracil on bone marrow was not increased in protein-deprived animals. On refeeding, there was a biphasic response in the degree of toxic effect on marrow. Animals refed for one day had significantly increased fluorouracil-related marrow abnormalities. However, animals refed for four days, when marrows were repleted, were partially protected from the drug's cytotoxic effects. The increased sensitivity in mice refed for one day was related to more GM-CFC in active DNA synthesis.     

Effects of growth hormone on leptin metabolism and energy expenditure in hemodialysis patients with protein-calorie malnutrition

The relationships among growth hormone (GH), leptin, and resting energy expenditure (REE) are not understood. It has been reported that in malnourished hemodialysis patients, GH increases muscle protein synthesis, a process that requires energy. The present study evaluated the arterial levels and the forearm exchange of leptin, as well as the REE of the same patients during their participation in the same study, in four sequential 6-wk periods: I, baseline; II, GH treatment; III, washout; and IV, GH + intradialytic parenteral nutrition. During periods II and IV, patients received GH (5 mg three times per week). REE rose by 5% in period II, declined during period III, and rose by 7% during period IV. Basal leptin levels were low (2.0 +/- 0.19 ng/L). Insulin and leptin levels, as well as leptin release from the forearm, were unchanged during periods I through III but rose (+ 36%; P: < 0.05) during period IV. Changes in arterial leptin were directly related to changes in forearm leptin release (P: < 0.002), indicating a role of leptin production by peripheral tissues on leptinemia. Changes in leptin release were directly related to insulin (P: < 0.001) and, less consistently, to insulin-like growth factor-binding protein-1 levels (P: < 0.02). Similarly, variations in leptin levels were directly related to insulin (P: < 0.01). Variations in REE were not related to variations in leptin or insulin levels but to changes in muscle protein synthesis (P: < 0.025). The data show that in malnourished hemodialysis patients, treatment with GH is not invariably associated with an increase in leptin production. An increase in leptin release by peripheral tissues and leptin levels occurs only in the setting of hyperinsulinemia. The increase in REE that is induced by treatment with GH is not dependent on changes in leptin but is largely accounted for by the energy cost of the stimulation of muscle protein synthesis.     

Immunosuppressive treatments: mechanisms of action and clinical use

Renal transplantation is the treatment of choice of end stage renal failure. It both improves the quality and the quantity of life compared to other techniques, such as hemodialysis. These results are partly related to the use of immunosuppressive therapy more effective and whose handling has improved over time. Advances in understanding the mechanisms of lymphocyte activation and the phenomena of rejection have in fact better defined the use of these treatments and their associations. Treatments can be broadly classified according to their characteristics (biological or chemical). Among chemical treatments, steroids are widely used, although the question of their avoidance or spearing is still a matter of debate. The cornerstone of immunosuppressive regimens remains the calcineurin inhibitors, characterized by a narrow therapeutic index and the need for therapeutic drug monitoring. Inhibitors of mammalian target of rapamycin (mTOR) have interesting antiproliferative effects that could be important against chronic allograft dysfunction and/or carcinogenesis. However, their safety profile makes them difficult to handle. Inhibitors of purine synthesis are largely based on inhibitors of inosine monophosphate dehydrogenase (IMPDH). Their effectiveness makes them privileged partners of other therapeutic classes. Among biological treatments, it is possible to separate the depleting and non depleting antibodies. Among the former, antithymocyte globulins are mainly active in T cells, whereas rituximab, a monoclonal anti-CD20, is active in B cells involved in the phenomena of humoral rejection. The non depleting antibodies are represented by anti-CD25, directed against the receptor for interleukin-2. In the near future it is likely that the belatacept, a costimulation blockade fusion protein will be used to allow calcineurin inhibitors sparing. Other immunosuppressive agents, acting at different levels of the immune response are being evaluated. In addition, advances in pharmacology offered hope of a better individualization of immunosuppressive therapies and better definition of therapeutic strategies used.     

Persistent impairment of insulin secretory response to glucose in adult rats after limited period of protein-calorie malnutrition early in life

The effect of a limited period of protein-calorie malnutrition in young rats on glucose tolerance, insulin secretory response to glucose, and tissue composition in the adult was studied. Three-week-old rats were weaned onto semisynthetic diets containing either 5% protein (low protein; LP) or 15% protein (control; C) and maintained for 3 wk on their respective diets. At 6 wk of age all rats were returned to a commercial rat chow diet (18% protein). Glucose tolerance, insulin secretory response to glucose, and the protein/DNA ratio in liver, skeletal muscle, heart, kidney, small intestine, and lung were investigated at 3, 6, and 12 wk of age. Rats receiving LP diet failed to gain weight, but growth resumed immediately when they were transferred to commercial rat chow. They did not, however, catch up with C rats. Glucose tolerance and insulin secretory response to glucose remained similar between 3 and 12 wk in C rats. In 6-wk-old LP rats, glucose tolerance was impaired, and the insulin secretory response to glucose was absent. At 12 wk of age the glucose tolerance of the LP rats had normalized, but the insulin secretory response was still blunted. In 6-wk-old LP rats there was an inhibition of the age-dependent increase in cell size, shown by lowered protein/DNA ratios in all tissues studied. This decrease in cell size persisted at 12 wk in liver, skeletal muscle, heart, and lung. We conclude that protein-calorie malnutrition early in life persistently impairs the insulin secretion. The persistently lowered protein/DNA ratios in many tissues may be related to this lowered capacity for insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure.

Hypoalbuminemia and muscle atrophy are frequently found in patients with chronic kidney disease (CKD) and patients being treated by dialysis. These abnormalities are usually attributed to malnutrition, meaning that they are caused by an inadequate diet. However, the evidence indicates that malnutrition is rarely the mechanism causing loss of protein stores. Instead, low values of serum albumin are closely related to the presence of inflammation and loss of muscle mass is attributable to activation of specific proteases. In uremic rodents and patients, the initial step in the loss of muscle protein is an activation of caspase-3. This cleaves the complex structure of muscle, and its action can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of muscle. The second step in uremia-induced loss of muscle protein is an activation of the ubiquitin-proteasome system, which rapidly degrades proteins released by caspase-3 cleavage of muscle proteins. Activation of both caspase-3 and the ubiquitin-proteasome system occur when there is suppression of the cellular signaling pathway activated by insulin/insulinlike growth factor 1, the phosphatidylinositol 3-kinase/Akt pathway. A potential therapeutic target for preventing loss of muscle protein is to stimulate activity of this signaling pathway.     

Immunosuppressive agents in transplantation: mechanisms of action and current anti-rejection strategies

Over the past century, the concept of interfering with the immune response at various sites by blocking the formation, stimulation, proliferation, and differentiation of lymphocytes has led to relentless development of new immunosuppressive drugs. These agents are associated with reduced risk of short- and long-term toxicity and have dramatically improved allograft and patient survival, especially in recipients of solid organ transplants. Current protocols in such patients are nearly all calcineurin-inhibitor based, using cyclosporine or tacrolimus, as part of dual, triple, or sequential therapy. This review focuses on agents currently in clinical use at transplant centers in United States. The drugs are described in terms of their basic mechanisms of action, therapeutic uses, clinical studies, and adverse effects. In addition, the efficacy and toxicity of a few promising new therapeutic approaches are examined. Finally, important challenges regarding pharmacological immunosuppression as it relates to solid organ and composite tissue allotransplantation are discussed.     

Immunosuppressive mechanisms of embryonic stem cells and mesenchymal stem cells in alloimmune response

Although both embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) are known to have immunosuppressive effects, the mechanisms of immunosuppression are still controversial. Both types of stem cells suppressed not only the proliferation but also survival of CD4⁺ T cells in vitro. They suppressed secretion of various cytokines (IL-2, IL-12, IFN-??, TNF-??, IL-4, IL-5, IL-1??, and IL-10), whereas there was no change in the levels of TGF-?? or IDO. Classic and modified transwell experiments demonstrated that immunosuppressive activities were mainly mediated by cell-to-cell contact. Granzyme B in the ESCs played a significant role in their immunosuppression, whereas PDL-1, Fas ligand, CD30 or perforin was not involved in the contact-dependent immunosuppression. However, none of the above molecules played a significant role in the immunosuppression by the MSCs. Interestingly, both stem cells increased the proportion of Foxp3⁺ regulatory T cells. Our results showed that both ESCs and MSCs suppressed the survival as well as the proliferation of T cells by mainly contact-dependent mechanisms and increased the proportion of regulatory T cells. Granzyme B was involved in immunosuppression by the ESCs in a perforin-independent manner.