Tissue advanced glycation end product deposition after kidney transplantation.

BACKGROUND: Tissue advanced glycation end products (AGEs) accumulate in chronic kidney disease (CKD) and are a measure of cumulative metabolic stress. Measurement of tissue AGEs by skin autofluorescence (SAF) correlates well with cardiovascular outcomes in dialysis patients. SAF levels in transplant recipients relative to CKD and dialysis patients have not been previously studied, and the impact of transplantation on SAF levels in dialysis patients is unknown. METHODS: SAF was measured using an AGE reader in 66 patients who had received a kidney transplant. Values were compared to those obtained in 1,707 patients with CKD stage 3 and in 115 patients on dialysis. RESULTS: Mean SAF in transplant recipients [2.81 ± 0.64 arbitrary units (AU)] was significantly lower than in patients on haemodialysis (3.73 ± 0.88 AU) and peritoneal dialysis (3.57 ± 0.75 AU; p < 0.001), but was no different from CKD stage 3 (2.79 ± 0.66 AU; p = 0.42). In the transplant group, SAF correlated most strongly with age (r = 0.316). There was no correlation between SAF and estimated glomerular filtration rate or renal replacement therapy vintage. A small cohort of patients with SAF recorded on dialysis and following transplantation showed a drop in SAF over a mean time of 16 months after transplantation. DISCUSSION: Tissue AGE values in kidney transplant recipients are significantly lower than in patients receiving dialysis and similar to those in patients with CKD stage 3. Our data suggest that transplantation may be associated with a reduction in tissue AGEs, and this might be an important component of the observed reduction in cardiovascular risk in transplant recipients compared to patients on dialysis.

T cell receptor V-segment frequencies in peripheral blood T cells correlate with human leukocyte antigen type.

We compared T cell receptor (TCR) V-segment frequencies in human leukocyte antigen (HLA) identical siblings to sibling pairs who differ at one or both HLA haplotypes using four V beta-specific and one V alpha-specific monoclonal antibody. In every one of nine families HLA-identical sibs had the most similar patterns of V-segment frequencies in their peripheral blood, whereas totally mismatched sibs were, in general, the most dissimilar; HLA haploidentical sibs tended to be intermediate between the two groups. The degree of similarity among HLA-identical sibs was comparable to that observed among three pairs of identical twins suggesting that HLA is the major genetic component influencing TCR V-segment frequency. Consistent with this observation, it was found that the frequency of T cells expressing particular V beta segments was skewed towards either CD4+ or CD8+ cells indicating that T cells expressing some V beta genes may be positively selected primarily by class I or class II major histocompatibility complex proteins. Finally, it was observed that individuals who express the HLA class I specificity, B38, tend to express high levels of V alpha 2.3+ cells among their CD8+ T cells. These observations represent definitive proof that human V-segment frequencies are profoundly influenced by the HLA complex.

Adaptation of fruit morphology to dispersal agents in a neotropical forest.

Two-thirds of 258 fruit species from Peruvian tropical forest belong to one of two classes: large orange, yellow, brown, or green fruits with a husk; or small red, black, white, blue, purple, or mixed-color fruits without a husk. The characteristics of the two fruit classes match the size, visual ability, and jaw morphology of mammals and birds, respectively, and the animals also prefer to eat one class of fruits. Thus, most plants in this forest seem to be adapted to seed dispersal by either of two distinct broad arrays of animal taxa.

Infanticide in black capuchin monkeys (Cebus apella nigritus) in Iguazú National Park, Argentina.

We report here one observed and two potential cases of infanticide during a brief period of 1 month after a dominant male replacement in one group of black capuchin monkeys in Iguazú National Park, Argentina. We also compile infant disappearances and demographic data in seven groups followed from 1-14 years. Behavioral and molecular data showed that the probability that an infanticidal male would kill his own progeny is very low in this species. Females that lost infants less than 6 months old had shorter interbirth intervals than females whose infants survived (14.12 ± 5.32 months, n=17 vs. 20.42 ± 5.65 months, n=34). Females whose infants die shortly after takeovers mate with the presumed infanticidal male during the most fertile days of their subsequent estrous periods giving this male a high probability of siring the new progeny. We recorded 181 proceptive periods and 52 births from 18 adult females in two groups. Most proceptive periods were concentrated during a conception season, but there was an increase in sexual behavior after male takeovers. Seven females copulated while pregnant after the observed male takeover, an unusual behavior in this species in years of group stability. Of 24 infants born during takeover years, 62.5% did not survive the first year, whereas only 22.5% of 80 infants died in years without male replacements. We found a significant positive association between infant mortality and male takeovers, but not with food provisioning. The main cause of infant mortality in this population is associated with male takeovers. Our results suggest that infanticide can have an important effect on the behavior of this species, selecting for female behaviors that function to reduce infanticide risk.

B-cell tolerance.

Autoreactive B cells are actively tolerized to more abundant self-antigens by a series of checkpoints involving receptor editing, deletion, anergy and competition for growth factors. In contrast, B cells reactive against rare, sequestered or tissue specific self-antigens remain functionally naïve. During an immune response, the autoimmune danger from these cells is countered by a variety of mechanisms comprising control of self-antigen presentation, limitation of immunogenic and tolerogenic costimuli including T cell help, homeostatic control of growth and strict regulation of germinal centre reactions. In this overview we consider how knowledge of these checkpoints may be used to gain a better understanding of transplant tolerance and the generation of alloantibodies.

Rational use of biological response modifiers in hematological malignancies--a review of treatment with interferon, cytotoxic cells and antibodies.

During the last decade the use of various biologic therapeutics/biological response modifiers in hematological malignancies has increased dramatically. Alpha-interferon (alpha-IFN) alone has clearly a substantial antitumoral effect in many hematological diseases. During the coming decade an improved effect will probably be seen by combination of alpha-IFN with cytostatics and other biologic therapeutics as well as by finding the optimal conditions when alpha-IFN should be used. Using unconjugated mouse monoclonal antibodies (MAb) only, an overall response rate of 38% was noted in patients with advanced disease. MAb therapy might be improved by using other Ig molecules, combination with cytokines and by finding an optimal dosage schedule. Only a few patients with hematological malignancies have been treated with IL-2/LAK cells. An overall response rate of 41% was seen in heavily pretreated patients. In all biologic therapeutics, an improved efficacy will be noted if patients with a low tumor burden and an intact immune system are treated. Immunization/vaccination with "tumor antigen" will probably contribute to an improved prognosis, especially in patients with minimal residual disease. There are several good candidates to be used as tumor antigens in hematological malignancies i.e. the idiotypic receptors on T and B cells. Biotherapy in hematological tumors has come to stay. However, due to the complexity of the effector system it will take a long time before an effective treatment concept is developed.

Equine serum lipids: serum lipids and glucose in Morgan and Thoroughbred horses and Shetland ponies.

Concentrations of serum phospholipids, triglycerides, total cholesterol, nonesterified fatty acids, and glucose were determined for 9 months (September, 1972, to May, 1973) in 19 fasting horses and ponies (8 Morgan horses, 7 Thoroughbred horses, and 4 Shetland Ponies). Morgan horses had higher concentrations of total lipid than did Thoroughbreds, although the relative proportions of each type of lipid were similar in the 2 breeds. Shetland Ponies had higher nonesterified fatty acid and lower glucose concentrations than did either breed of horse. In both breeds of horses, concentrations of serum triglycerides in the cold months (December to March) were lower than those in the warm months. In the Shetland Pony, there was no seasonal variation in triglycerides, but a significant increase was seen in concentration of nonesterified fatty acids in the cold months. The significance of these findings is discussed.

Equine serum lipids: lipid composition and electrophoretic mobility of equine serum lipoprotein fractions.

The serum lipoprotein fractions from 5 Morgan and 5 Thoroughbred horses were isolated by preparative ultracentrifugation, chemically analyzed for lipid composition, and studied by 2 methods of polyacrylamide gel electrophoresis to determine electrophoretic mobility. Breed differences were not seen in the relative percentages of the lipid classes found in the various fractions. Normally, horses, like most animals, carry the majority of their lipid in high-density lipoproteins. Electrophoretically, the only difference seen between breeds occurred on disc electrophoresis where the extra band, which is characteristic of lipoprotein profiles of Morgans, was found in the high-density lipoprotein fraction.

Renal infarction in patients presenting with suspected renal colic.

Acute renal infarction is a serious medical emergency. The diagnosis is often delayed or missed as it is not common. Hence, the exact incidence of acute renal infarction is not known. Failure to consider renal infarction in the initial differential diagnosis results in a delay in diagnosis and treatment, which in turn leads to permanent loss of renal function. We present two cases of acute kidney infarction that were initially treated as renal colic. In addition, we present a third case when a kidney was saved with reperfusion therapy.

Predicting the frequency of food-related agonism in white-faced capuchin monkeys (Cebus capucinus), using a novel focal-tree method.

Food abundance and distribution have played a central role in the conceptual theory of primate socioecology [Janson, Behaviour 105:53-76, 1988; Isbell, Behavioral Ecology 2:143-155, 1991; Sterck et al., Behavioral Ecology and Sociobiology 41:291-309, 1997; van Schaik, In: Standen V, Foley RA, editors, Comparative Socioecology. Oxford: Blackwell. p 195-218, 1989]. This theory predicts that agonistic ("contest") competition should occur when food is distributed in discrete, defensible patches; in contrast, when food sources are distributed uniformly or randomly, non-agonistic ("scramble") competition is expected. Primatologists usually measure resource density and patchiness from a botanical perspective, ignoring the biology of the animal being studied. Such an approach may be irrelevant in terms of how animals view the dispersion of resources. Using a novel focal-tree method that measures resource availability on a scale that is both spatially and temporally relevant to the animal under investigation, we take a cost-benefit approach to predict the frequency of food-related agonism in white-faced capuchin monkeys (Cebus capucinus) from 11 ecological and social variables. We retained four variables in the regression model: two representing the opportunity for aggression (i.e., feeding bout length and the number of feeding adult females), and two representing opportunity costs (i.e., fruit abundance and the number of potential feeding sites in the focal tree). The results of this study indicate that the amount of food-related aggression in white-faced capuchins can be predicted by variables representing the costs and benefits of contesting a food resource.

Limited peripheral T cell anergy predisposes to retinal autoimmunity.

Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

Signals from a self-antigen induce positive selection in early B cell ontogeny but are tolerogenic in adults.

Positive and negative signals from self-Ags shape the B cell repertoire and the development of distinct B cell subsets, but little is known about what distinguishes these signals. To address this question, we have studied the development of anti-hen egg lysozyme MD4 Ig transgene B cells while systematically varying the level, distribution, and timing of exposure to different forms of hen egg lysozyme as a self-Ag. This process has allowed us to explore the effects of Ag independent of BCR specificity. Our findings show how the selection of autoreactive B cells is a competitive process involving immunogenic and tolerogenic forms of self-Ags. Due to a developmental switch during B cell ontogeny, autoreactive anti-hen egg lysozyme MD4 Ig transgene B cells are negatively selected by self-Ags in adult bone marrow but susceptible to positive selection by some of the same self-Ags in fetal and neonatal life. However, the persistence of B1 cells and IgM autoantibodies from early ontogeny enables autoreactive B cells from the adult bone marrow to escape negative selection. Our data suggest that this rescue may be due to the clearance or masking of self-Ag by IgM autoantibody. We discuss the implications of these findings in terms of B cell selection and the maintenance of self-tolerance during early and adult life.

Spontaneous B cell hyperactivity in autoimmune-prone MRL mice.

The MRL-lpr/lpr mouse strain is a commonly used model of the human autoimmune disease systemic lupus erythematosus (SLE). Although much is known about the contribution of the lpr Fas mutation to B cell tolerance breakdown, the role of the genetic background of the MRL strain itself is less well explored. In this study, we use the MD4 anti-hen egg lysozyme Ig (IgHEL) transgenic system to explore B cell function in MRL+/+ and non-autoimmune mice. We demonstrate that MRL IgHEL B cells show spontaneous hyperactivity in the absence of self-antigen, which is associated with low total B cell numbers but an expansion of the marginal zone B cell population. However, B cell anergy is normal in the presence of soluble lysozyme [soluble hen egg lysozyme (sHEL)], and MRL IgHEL B cells undergo normal elimination in the presence of sHEL when competing with a polyclonal C57BL/6 B cell repertoire. We conclude that B cell hyperactivity may contribute to the autoimmune phenotype of MRL+/+ and MRL-lpr/lpr strains when it initiates antibody responses to rare or sequestered antigens that are below the threshold for tolerance induction, but that there is no B cell intrinsic defect in anergy in MRL mice.

CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions.

Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.

Biology of monoclonal antibodies in tumor therapy.

This paper gives an overview of the biology of monoclonal antibodies in tumor therapy. The complexity of the monoclonal antibody concept is discussed with functional aspects on tumor antigen, antigen binding, Ig isotypes and effector mechanisms involved.

Morphological and behavioral adaptations for foraging in generalist primates: the case of the cebines.

In addition to being frugivorous, Cebus and Saimiri stand out among the New World primates of similar body size in being heavily dependent on animal matter for protein (faunivory). A detailed description of the morphology and behavior of the two genera is presented with the object of evaluating the interaction and respective contributions of morphological and behavioral adaptations to foraging patterns. Our conclusions include the following: First, body size is extremely important in explaining the observed variation in diet. Second, the emphasis on faunivory is facilitated more by behavioral than by morphological specialization. Third, whatever morphological specializations are present, particularly in Cebus, are probably favored by diet at the most food-depauperate time of year. Fourth, although morphology may well reveal what a primate may potentially eat, to map this potential onto actual diet requires a detailed knowledge of its natural ecosystem. Finally, we consider whether the behavioral data support the tenuous morphological evidence for grouping Cebus and Saimiri within the clade Cebinae.

When will the stork arrive? Patterns of birth seasonality in neotropical primates.

We review and discuss the ultimate and proximate causes of birth seasonality in Neotropical primates and the seasonal patterns shown by each genus within this group. Our review of the literature shows that most New World monkey populations studied so far show some degree of birth seasonality. Photoperiod is the most important proximate cue used by populations living at relatively high latitudes to time their reproductive events, but almost nothing is known about the proximate factors used by those near the equator. The findings are consistent with the hypothesis that food availability is the most important ultimate cause of birth seasonality. Predation seems to promote birth synchrony in some species (e.g., squirrel monkeys). Multiple regression ANCOVA was used to estimate how the degree of birth seasonality is affected by ecological and life history variables. The ANCOVA model shows that three factors affect the degree of birth seasonality: diet, latitude, and body size. Folivores (howlers) are less seasonal than frugivores and insectivores. The degree of seasonality increases with latitude and shows a humped relationship with body size, peaking at 1.66 kg body mass. This last relationship was expected since small bodied species have to pay a cost (in terms of time lost) by being seasonal on a yearly basis, and large species are buffered against fluctuations in food availability due to their large body mass. To understand which of three alternative birth strategies is followed by each species (reduce energy stress during peak lactation, wean infants during peak food availability, or store reserves during peak energy availability), we compared the location of the birth peak in relation to the peak in food-availability for those populations from which data were available. Most species conform to the typical pattern of births concentrated before the peak in food availability, allowing peak lactation (small-sized species) or weaning (capuchins) to take place before the start of the lean season. The pattern of births of the atelines is consistent with the weaning hypothesis. However, since they give birth during the lean season, this pattern is also consistent with an alternative strategy.

An analysis of alpha/beta TCR V gene expression in the human thymus.

We have previously analysed alpha/beta T cell receptor (TCR) V gene usage in CD4+ and CD8+ subpopulations from human peripheral blood lymphocytes (PBL) and umbilical cord blood, and described a biased usage of some of the TCR V beta genes towards the CD4+ subpopulation. In this report, the TCR V gene usage in single positive (SP) CD4+ or CD8+ human thymocytes was analysed. Three previously described mAb with a biased usage in PBL and umbilical cord blood also had a skewed reactivity towards the CD4+ subpopulation in SP human thymocytes. Thus, in all 12 cases V beta 5.1 and V beta 6.7, and in 11/12 cases V beta 12 were preferentially used in the CD4+CD8-, compared to the CD4-CD8+ thymic subpopulation. Altogether, these results suggest a selection process in the thymus, supposedly through the positive influence of MHC class II determinants, to be responsible for this non-random, skewed TCR V gene usage.

Biased expression of individual T cell receptor V gene segments in CD4+ and CD8+ human peripheral blood T lymphocytes.

The expression of seven different alpha and beta gene segments of the T cell receptor on normal human CD4+ and CD8+ T lymphocytes, respectively, was examined using V gene-specific monoclonal antibodies. We found a statistically significant (p less than 0.001) bias of the expression of four V gene products towards the CD4+ subpopulation. In every individual analyzed, the V beta 5.1 gene segment was expressed to a higher degree among CD4+ compared to CD8+ cells, with a median value of 4.8% among CD4+ cells and 1.5% among CD8+ cells. There was also a statistically significant skewness in the usage of the V beta 6.7, V beta 8 and V beta 12 gene segments towards the CD4+ T cell population, but not as dominating as for the V beta 5.1. Lymphocytes from umbilical cord blood showed similar skewed reactivities for the V beta 5.1, V beta 6.7 and V beta 12-specific monoclonal antibodies. Aspects of positive and negative selection, as possible explanations for these findings, are discussed.