Varuna Aluvihare

Regulatory T cells mediate maternal tolerance to the fetus

Pregnancy constitutes a major challenge to the maternal immune system, as it has to tolerate the persistence of paternal alloantigen. Although localized mechanisms contribute to fetal evasion from immune attack, maternal alloreactive lymphocytes persist. We demonstrate here an alloantigen-independent, systemic expansion of the maternal CD25+ T cell pool during pregnancy and show that this population contains dominant regulatory T cell activity. In addition to their function in suppressing autoimmune responses, maternal regulatory T cells suppressed an aggressive allogeneic response directed against the fetus. Their absence led to a failure of gestation due to immunological rejection of the fetus.

B cells and professional APCs recruit regulatory T cells via CCL4

Using gene expression profiling, we show here that activation of B cells and professional antigen-presenting cells (APCs) induces the expression of common chemokines. Among these, CCL4 was the most potent chemoattractant of a CD4+CD25+ T cell population, which is a characteristic phenotype of regulatory T cells. Depletion of either regulatory T cells or CCL4 resulted in a deregulated humoral response, which culminated in the production of autoantibodies. This suggested that the recruitment of regulatory T cells to B cells and APCs by CCL4 plays a central role in the normal initiation of T cell and humoral responses, and failure to do this leads to autoimmune activation.

Nef Triggers a Transcriptional Program in T Cells Imitating Single-Signal T Cell Activation and Inducing HIV Virulence Mediators

Gene expression profiling was used to explore the role of Nef in HIV. Nef induces a transcriptional program in T cells that is 97% identical to that of anti-CD3 T cell activation. This program is inhibited in the presence of cyclosporin. A requirement for TCR zeta and ZAP-70 is demonstrated for formation of the complete profile. Among eight factors particular to the anti-CD3 activation profile are IL16 and YY1, negative regulators of HIV transcription. In contrast, Nef exclusively upregulates factors positively regulating HIV, including Tat-SF1, U1 SNRNP, and IRF-2. New genes associated with Nef include CDK9, the induction of which enhances Tat function. Thus, Nef acts as a master switch early in the viral life cycle, forcing an environment conducive to dynamic viral production.

Acceleration of intracellular targeting of antigen by the B-cell antigen receptor: importance depends on the nature of the antigen–antibody interaction

The B‐cell antigen receptor (BCR) internalizes bound antigen such that antigen‐derived peptides become associated with emigrating major histocompatibility complex (MHC) class II molecules for presentation to T cells. Experiments with B‐cell transfectants reveal that BCR confers a specificity of intracellular targeting since chimeric antigen receptors which internalize antigen by virtue of a heterologous cytoplasmic domain do not necessarily give rise to presentation. In contrast, however, previous studies have shown that antigen binding to irrelevant cell surface molecules (e.g. transferrin receptor, MHC class I) can ultimately lead to presentation. The solution to this paradox appears to be that the intracellular targeting by BCR actually reflects an acceleration of antigen delivery. Depending on the nature of the BCR–antigen interaction, this accelerated targeting can be essential in determining whether or not internalization leads to significant presentation. Physiologically, the accelerated delivery of antigen by BCR could prove of particular importance early in the immune response when antigen–BCR interaction is likely to be poor.

Tolerance, suppression and the fetal allograft

In solid organ transplantation the recipient immune system recognises foreign alloantigens expressed by the graft. This results in an immune attack of the transplanted organ leading to rejection, which can be prevented only by therapeutic immunosuppression. During pregnancy the fetus should also be rejected by the maternal immune system, since it expresses antigens derived from the father. Whilst the immune system retains the ability to respond to foreign antigen, tolerance mechanisms ensure that inappropriate responses against self-antigen are prevented. Maternal immune aggression directed against the fetus is partly inhibited by peripheral tolerance mechanisms that act locally to deplete cells capable of attacking the fetus. Other local mechanisms inhibit the pathways that cause tissue damage after immune activation. Recent studies in mice and humans indicate that the maternal immune system undergoes a more systemic change that promotes materno-fetal tolerance. Naturally occurring regulatory T cells, which are commonly associated with maintaining tolerance to self-antigens, can also suppress maternal allo-responses targeted against the fetus. We review the mechanisms that mediate materno-fetal tolerance, with particular emphasis on changes in regulatory T cell function during pregnancy and discuss their implications.

The role of regulatory T cells in alloantigen tolerance

Summary:  The diversification mechanism used by the adaptive immune system to maximize the recognition of foreign antigens has the side effect of generating autoreactivity. This effect is counteracted by deletion of cells expressing receptors with high affinity to self (central tolerance) and suppression of autoreactive cells by regulatory T cells (Tregs; peripheral tolerance). This understanding led to the notion that Tregs represent a specialized subset of autoreactive T cells with inhibitory function. The process of generating a diverse repertoire of receptors recognizing antigen presented by major histocompatibility complex (MHC) intrinsically leads to the generation of cells recognizing foreign MHC (alloantigen). The precursor frequency of T cells responding to alloantigen is substantially higher than that responding to any exogenous antigen. The only physiological context in which this becomes a problem is placental viviparity. Although the maternal immune system has no intrinsic mechanism to distinguish between a pathogen and paternally derived fetal alloantigen, it has to neutralize the former and tolerate the latter. We review the function of Tregs from this perspective and propose that they may have evolved to promote tolerance to alloantigen in the context of pregnancy.

Liver transplantation in patients over 60 and 65 years: An evaluation of long‐term outcomes and survival

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged > 65 yr (group 1) who underwent transplantation between 1988 and 2003 at Kings College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n = 137) and 202 time‐matched control patients with chronic liver disease aged between 18‐59 yr (group 3). Patient survival at 30‐days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P = not significant [NS]). At 1‐yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P = NS), and at 5‐yr patient survival was comparable (73%, 80%, and 78%, respectively) (P = NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P = 0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P = 0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5‐yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients >65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken. Liver Transpl 13:1382–1388. 2007.

The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis.

An association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognized. However, the disease course of IBD following liver transplantation (LT) for PSC remains ill‐defined.

Systematic review: the role of liver transplantation in the management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Liver transplantation offers a potential cure for this otherwise devastating disease. The selection of the most appropriate candidates is paramount in an era of graft shortage.

Human Liver Regeneration Is Characterized by the Coordinated Expression of Distinct MicroRNA Governing Cell Cycle Fate

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long‐term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration‐linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration‐linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.