Dendritic cells mediate tolerance to vascularized grafts

The primary goal in clinical transplantation is tolerance to transplant antigens. Although much has been learned over the past decade about the various cell populations involved in transplant rejection, the cell sub-populations involved in the induction and maintenance of transplant tolerance remain unidentified. This is due in part to the difficulty in defining the interactions between diverse antigen-presenting cells and T-cell subsets with disparate trafficking patterns. Now, an article by Ochando et al.¹ has identified plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4⁺CD4⁺CD25⁺Foxp3⁺ regulatory T cells (T_reg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral T_reg-cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced T_reg-cell development and prolonged graft survival. Thus, in tolerogenic conditions, alloantigen-presenting pDCs homed to the lymph nodes, where they mediated alloantigen-specific T_reg-cell development and allograft tolerance. In an accompanying commentary,² Qizhi Tang and Jeffrey A Bluestone point out that dendritic cells, in addition to initiating immune responses, also influence regulatory T-cell activity and homeostasis. They note that functional outcomes of dendritic cell–T cell interactions depend on the immunological context of their encounter. (¹Nat Immunol 2006; 7: 652–662. ²Nat Immunol 2006; 7: 551–553)

Detlef Schlöndorff

May-Grünwald–Giemsa (MGG) staining and live fluorescent images of splenic B cells, splenic pDCs and peritoneal macrophages (M).

Molecular profiling of transplanted organs improves clinical diagnoses

Changes in the function of transplanted organs are often assessed by histological analysis of small biopsies. Although this is still considered the gold standard for diagnosis of acute transplant rejection, comparisons between histological diagnoses of biopsies and of the whole organ at autopsy in heart transplants show that the overall sensitivity of endomyocardial biopsy is only about 70%, and that a substantial number of rejections can be missed. In addition, infection of the transplanted organ may also occur, and histology of biopsies may not discriminate well between a rejection and an immune response involved in fighting infection. Yet discrimination is essential, because the treatment for the two conditions is different. Morgun et al. tested whether molecular profiling by microarray analysis of gene expression patterns would identify infections. They studied cardiac allografts as a model transplant, and Chagas's disease (infection with Trypanosoma cruzi) as a model infection. In Latin America, many heart recipients receive transplants because of chronic heart failure resulting from Chagas's disease, and relapse is one of the most frequent post-transplantation complications. The authors analyzed mRNA amplified from biopsy samples taken from heart recipients with cases of rejection, no rejection, or infection. They found specific molecular profiles that discriminate among patients undergoing rejection, no rejection, or infection. A set of genes whose expression patterns were typical of acute rejection and another set of genes that discriminated between rejection and T. cruzi infection were identified. These sets revealed acute-rejection episodes up to 2 weeks earlier and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the two sets of predictive genes were able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. Thus, this approach may be useful for identifying infections that are universally encountered and for transplanted organs other than the heart. (Circ Res 2006; 98: 1564)

Juan Oliver

Nephritogenic lupus antibodies recognize fragments of apoptotic intraglomerular cells

Antibodies to double-stranded DNA (dsDNA) represent a classification criterion for systemic lupus erythematosus, and sub-populations of these antibodies are involved in lupus nephritis. It is unclear what separates nephritogenic from non-nephritogenic anti-dsDNA antibodies. Further, it is still unresolved whether glomerular target antigens are constituted by nucleosomes or non-nucleosomal glomerular structures. It has been previously shown that antibodies eluted from murine nephritic kidneys recognize nucleosomes. In a new study, Kalaaji et al. examined the structures that bind nephritogenic autoantibodies in vivo. They used transmission electron microscopy, immune electron microscopy and colocalization immune electron microscopy together with antibodies to dsDNA, to histones and transcription factors, or to laminin. Their results indicate that glomerular basement membrane-associated nucleosomes are the target structures for the nephritogenic autoantibodies. Furthermore, TdT-mediated dUTP nick end-labeling or caspase-3 assays demonstrate that lupus nephritis is linked to intraglomerular cell apoptosis. The data suggest that nucleosomes are released by apoptosis and associate with glomerular basement membranes, which may then be targeted by pathogenic anti-nucleosome antibodies. Thus, apoptotic nucleosomes may represent both inducer and target structures for nephritogenic autoantibodies in systemic lupus erythematosus. (Am J Pathol 2006; 168: 1779–1792)

Juan Oliver

Morphological analyses of nephritic glomeruli of B/w16 by transmission electron microscopy and colocalization immune electron microscopy.

Prevention of C5 activation ameliorates glomerulonephritis in factor H deficiency

Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory disease for which there is no effective therapy; about half of patients progress to end-stage renal failure within a decade. The disease is characterized by intramembranous glomerular basement membrane (GBM) deposits together with C3, C5 and C9 staining along the GBM in the absence of immunoglobulin. Deficiency of factor H (a serum protein that inhibits the alternative pathway of complement activation) in mice, pigs and humans is associated with MPGN type II. In factor H deficiency, there are unhindered alternative-pathway activation and markedly reduced C3 levels in plasma. MPGN has also been reported in individuals with dysfunctional C3 molecules and in an individual with an autoantibody against factor H. Patients with MPGN type II also develop macular drusen, a feature of age-related macular degeneration that has recently been associated with factor H mutations.

Abnormal factor H function appears to underlie the pathogenesis of many cases of human MPGN type II, but the role of other components of the alternative complement pathway has not been studied. Using factor H-deficient mice (Cfh-/-), which spontaneously develop MPGN that depends on activation of C3, Pickering et al. examined the role of C5 activation in the development of the glomerulonephritis. They found that mice deficient in both C5 and factor H still developed MPGN but displayed reduced mortality and glomerular cellularity in comparison with mice deficient in factor H alone. Second, to mimic disease flares that may occur in patients with MPGN, they investigated how Cfh-/- mice with MPGN responded to an additional nephrotoxic insult. They found that these mice had increased susceptibility to heterologous nephrotoxic nephritis and that administration of a monoclonal anti-C5 antibody was protective. Thus, their data show a modifying pathogenic role for C5 activation in the development of spontaneous MPGN and in acute renal injury. These findings are relevant to the treatment of individuals with MPGN type II and C3 dysregulation. The authors suggest testing the efficacy of anti-human C5 antibody therapy. (Proc Natl Acad Sci USA 2006; 103: 9649–9654)

Juan Oliver