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.

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.

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.

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.

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.

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.

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.

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.

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.

T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden.

The T cell receptor (TCR) variable (V) gene repertoire was analyzed in patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 17), multiple myeloma (MM) stage I (n = 16), MM stages II/III (n = 31) and age-matched controls (n = 27) by immunofluorescence and flow cytometry using a panel of mouse monoclonal antibodies (mAb) (n = 10) against TCR V alpha and V beta gene products. T cell expansion was defined as a value > or = thrice the normal median value for each respective TCR V mAb. Fifty-three percent of all patients displayed CD8+ expansion(s) as compared to 30% of age-matched controls (p < 0.001). Within the CD4 subset, 18% of the patients displayed T cell expansion(s) in comparison to 11% of the controls (not significant). Interestingly, the CD8+ expansion(s) were more frequently noted in patients with a low tumor burden (MGUS/MMI) (73%) as compared to those with advanced disease (MM II/III) (32% and control donors (30%) (p < 0.01). Likewise, multiple CD8+ expansions (two or more) were more common in MGUS/MM I patients than in MM II/III and controls (p < 0.01). The T cell expansions were stable over time in patients with a stable disease. A high degree of clonality of the expansions was detected by TCR CDR3 fragment length analysis, determination of J beta gene usage and nucleotide sequencing. The frequent finding of oligoclonal CD8+ T cell expansions in patients with a low tumor mass, but not in patients with advanced disease justifies further work in order to identify the relevance of expanded CD8+ T cells. In one patient with T cell reactivity against the autologous myeloma idiotype, two expansions within the CD8 population (V beta 3 and V beta 5.2 respectively) displayed no reactivity against the idiotype. Instead, idiotype recognition was confined to a CD8 non-expanded V beta 22+ T cell population, with a highly restricted TCR usage (CDR3 fragment length analysis).

Strict adherence to a common rank order of T-cell receptor V beta usage in human leucocyte antigen disparate individuals.

In order to investigate the T-cell receptor (TCR) V beta usage in different T-cell subsets, the authors performed flow cytometric analyses using a large panel of TCR V beta-specific monoclonal antibodies on CD4+, CD8+ CD28+ and CD8+ CD28- T cells from 15 random blood donors, six umbilical cords and seven human leucocyte antigen (HLA) identical non-twin sibling pairs. The authors found that the proportion of T cells expressing each V beta gene product was similar within CD4+ and CD8+ CD28+ T cells from all samples studied. For these T-cell subsets a rank order of V beta usage could be identified which was adhered to by all donors. In contrast, within CD8+ CD28- T cells a wide variation of V beta usage was found between individuals, and no rank order correlation could be detected. Members of HLA identical sibling pairs were found to be no more similar in their usage of V beta gene products than pairs of HLA disparate random blood donors. Groups of individuals sharing HLA antigens were no different from the groups not sharing such antigens in their usage of V beta segments. The results suggest that HLA polymorphisms play no more than a minor part in determining TCR V beta usage.

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.

T-cell receptor V-gene usage in synovial fluid and synovial tissue from RA patients.

The question of whether there is a preferential use of certain V genes in T cells entering an inflamed joint has hitherto been studied mainly using unfractionated cells from synovial fluid and tissue respectively, and no clear answer to the question has yet been provided. Concomitantly, evidence has been provided that the use of V genes may differ considerably between CD4+ and CD8+ T cells, and consequently that detection of biased V-gene expression within an inflammatory lesion may require separate analysis of the two T-cell subsets. In this paper we have therefore studied T-cell receptor V-gene expression in rheumatoid arthritis by means of double stainings of synovial fluid and blood for available anti-TCR monoclonal antibodies and antibodies to CD4 and CD8, respectively. Double stainings were also performed with anti-TCR antibodies and antibodies to activation markers HLA-DR and IL-2R. A certain bias towards the preferential use of certain V genes was seen particularly in the synovial fluid samples within both the CD4+ and CD8+ T-cell populations, but no uniform pattern was evident among the 35 patients investigated.

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.

Nearly identical T-cell receptor V-gene usage at birth in two cohorts of distinctly different ethnic origin: influence of environment in the final maturation in the adult.

We have previously analysed the T-cell receptor (TCR) V-gene usage in peripheral blood T lymphocytes from a group of healthy Scandinavians, and described a biased representation (i.e. a statistically significant higher median representation) for some of the TCR V genes towards the CD4+ subpopulation. In a subsequent study the usage of the same V genes was analysed in single positive (CD4+ CD8- and CD4- CD8+) human thymocytes, and a similar type of skewness was noted. These observations might be explained by an influence of the specificity of the TCR of thymocytes on the maturation into the CD4+ or the CD8+ lineage. Such a model would assume an interaction between a common determinant on the major histocompatibility complex (MHC) class I or class II molecules, or with a peptide that is preferentially presented by either of the two molecules, and the TCR on the maturing thymocyte. To investigate the possible influence of a different genetic background and environment on skewed TCR V-gene representation, we have in this study analysed the TCR V-gene usage in peripheral blood and umbilical cord blood lymphocytes obtained from Asians, with a different ethnic and environmental background from our previous Scandinavian subjects. In the umbilical cord blood lymphocytes the TCR V-gene usage was close to identical between the two different ethnic groups in both CD4+ and CD8+ subpopulations. Analysing the peripheral blood lymphocyte (PBL) TCR V-gene usage, we found that three of the four monoclonal antibodies (MoAb) with a biased reactivity towards the CD4+ subpopulation in the Scandinavian group also showed a similar skewed reactivity in this study. Thus, the majority of the TCR V genes were used in a similar way. Some minor but definite discrepancies could be detected when comparing TCR V-gene usage in adult individuals from these two different ethnic groups. These differences could be inferred to be due to selective peripheral expansion through environmental pressure of T cells utilizing a specific V beta gene segment. We conclude that a striking preservation of biased TCR V-gene usage does exist in humans of distinctly different ethnic origin.

Analysis of J beta gene segment usage by CD4+ and CD8+ human peripheral blood T lymphocytes.

Certain T cell antigen receptor V gene products in man have been shown by us and others to display a reproducible bias for preferential expression in CD4+ or CD8+ T cell subsets. In order to investigate whether such a skewed representation of V gene segments is also present at the J gene segment level, we tested the relative J beta gene usage by V beta 5.1 + T cells, as this V beta gene is biased towards CD4+ T cell expression in virtually all individuals. To analyze the usage of the 13 J beta gene segments, we developed a new approach using V beta 5.1 and C beta specific oligonucleotides as 5' and 3' primers respectively for polymerase chain reaction (PCR) amplification of cDNA derived from CD4+ or CD8+ peripheral blood lymphocyte (PBL) T cells. The PCR products were visualized for reactivity with individual J beta 1.1-1.6 and J beta 2.1-2.7 32P-labelled oligonucleotide probes using autoradiography and quantitative gel-scanning. Eleven normal blood donors provided the PBL T cells. The results showed that in every individual's V beta 5.1+ T cell populations (CD4 and CD8), all V beta/J beta combinations were used although at varying but reproducible levels for each J beta gene. Thus, no discernible disallowance of combinations existed. Moreover, we could show that six of 13 J beta genes were unequally expressed when compared in pairs with regard to expression in CD4+ and CD8+ T cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

T-cell receptor variable (V) gene usage by lymphoid populations in T-cell lymphoma.

A panel of monoclonal antibodies specific for TcR V gene families was used to study TcR V region expression in 28 cases of malignant and reactive T-cell expansions including four cases of mixed cellularity Hodgkin's disease (HD) and five reactive cases. TcR V beta 5 gene products were represented in three cases of lymphoblastic malignancy (V beta 5.1, V beta 5.2) and two cases of peripheral T-cell lymphoma (PTCL) (V beta 5.1). In the PTCL cases, the expanded family was found in the absence of clonal TcR gene rearrangements and in one of these cases with Ig JH and Ck clonal gene rearrangements consistent with the presence of a phenotypically and histologically undetectable clonal B-cell population. In a third PTCL case not investigated for genotype, the TCR V alpha 12 family was overrepresented. Expanded TcR V alpha 2 and V beta 5.1 families were identified in HD and V beta 8 and V beta 5.2/V beta 5.3 families in a reactive lymph node and CD3 and CD8-positive blood lymphocytosis respectively. Further study of PTCL and related entities are needed to establish whether expanded TcR families are common in those cases that fail to exhibit clonal TcR gene rearrangement.

Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3.

The alpha/beta T cell receptor (TcR) V gene usage of bronchoalveolar lavage (BAL) lymphocytes and peripheral blood lymphocytes (PBL) from 11 sarcoidosis patients and 4 healthy controls was investigated, using eight alpha/beta TcR V gene product-specific monoclonal antibodies (mAb). Twenty-seven percent (3/11) of the sarcoidosis patients had a highly significant increase in V alpha 2.3+CD4+ T lymphocytes in the bronchoalveolar space, while displaying normal frequencies of these T cells in peripheral blood. The reactivities with the remaining seven TcR mAb were normal. In the control group, no compartmentalization of any T cells was seen. Four of the patients expressed the HLA-DR3 (w17), DQw2 haplotype. Interestingly, the three patients with distinct signs of compartmentalized V alpha 2.3+CD4+ T cells all expressed this HLA haplotype. Additionally, a fourth patient with pronounced, although less significant, accumulation of V alpha 2.3+CD4+ T cells in the lung, was also HLA-DR3(w17), DQw2+. Expression of V alpha 2.3+CD4+ T cells in BAL of these patients correlated with clinical disease, as revealed on re-analyzing the four patients after 6 months or longer. Predominant TcR V alpha 2.3 gene usage in compartmentalized CD4+ BAL T lymphocytes, linked to HLA-DR3(w17), DQw2 haplotype, may thus indicate presence of a specific antigen localized to the lungs of sarcoidosis patients.