The Escherichia coli heat-labile enterotoxin B subunit protects from allergic airway disease development by inducing CD4+ regulatory T cells.

The B subunit of E. coli heat-labile enterotoxin (EtxB) protects against the development of T helper type 1 (Th1)-mediated autoimmune pathologies in mice. Protection was transferable with splenic CD4(+) T cells and was less effective following CD25 depletion; implying a T regulatory cell (Treg)-mediated process. We hypothesized that if this were the case, then EtxB would also control a Th2-mediated disorder. We tested the effect of EtxB treatment on asthma development in ovalbumin (OVA)-sensitized mice. EtxB treatment diminished eosinophilia in bronchoalveolar lavage samples, reduced OVA-specific immunoglobulin E and interleukin 4 production locally and systemically, and reduced airway hyper-reactivity. EtxB induced a dose-dependent increase in Foxp3(+)CD4(+) T cells, and adoptive transfer of splenic CD4(+) T cells partially suppressed lung pathology. Importantly, EtxB treatment increased OVA-specific CD4(+)Foxp3(+) T cells in the lung and systemically. These data demonstrate that EtxB modulates the differentiation of allergen-specific T cells causing inducible Treg induction and preventing disease.

Long-term post transplant alloantibody monitoring: a single center experience.

Between 2000 and 2010, 4241 sera from 597 renal transplant (RTx) recipients were monitored for DSA development. The patients were selected in the absence of immunological memory to donor HLA before RTx and were divided into two groups: the historic group, consisting of patients transplanted before December 1996 and the study group, consisting of those transplanted after December 1996. Ninety-two out of 597 (15.4%) patients developed de novo DSA post-RTx, while 196 had third party anti-HLA antibodies. DSA were more frequent in the historic group compared with the study group (P < 0.001). Anti-HLA class-III DSA predominated in both groups (84.6% vs. 69.7%) and were directed preferentially against donor HLA-DQ (65/92,70.6%). Recipients of class II-incompatible grafts developed DSA more frequently than those receiving class II-compatible grafts (P = 0.003). DSA production was not different between pre-sensitized and non-sensitized patients (P = 0.842). DSA class I (HR = 31.78), DSA class II (HR = 20.92), and non-DSA (HR = 5.94) were the only independent predictors for graft failure. In conclusion, this study shows the results of long-term post-transplant alloantibody monitoring, and confirm the strong association of DSA and graft loss. Protocols that remove anti-HLA antibodies from RTx recipients may benefit allograft survival.

Attenuation of TNF-driven murine ileitis by intestinal expression of the viral immunomodulator CrmD.

Tumor necrosis factor α (TNFα) is a key pathogenic factor in Crohn's disease and rheumatoid arthritis. TNF(ΔARE) mice express high levels of TNFα and present Crohn's-like ileitis and arthritis. Alterations in the chemokine network could underline the TNF-driven ileitis. The aim of this study was to evaluate the role of TNF and chemokines in ileitis using ectromelia virus cytokine response modifier D (CrmD), a protein that binds TNFα and a limited number of chemokines. We generated transgenic mice expressing CrmD in intestinal epithelial cells (vCrmD mice) and crossed them with the TNF(ΔARE) mice to test whether CrmD could affect TNF-driven inflammatory processes. During homeostasis, only the number of B cells in the lamina propria was reduced by CrmD expression. Interestingly, CrmD expression in the intestine markedly attenuated the inflammatory infiltrates in the ileum of TNF(ΔARE) mice, but did not affect development of arthritis. Our results suggest that CrmD affects development of ileitis by locally affecting both TNF and chemokine function in the ileum.

Humoral sensitization against rejected grafts: specific antibodies to graft immunogenic amino acid triplets.

Humoral sensitization against immunogenic amino acid (aa) triplets expressed on a rejected graft was analyzed in 83 retransplant candidates. All patients had lost a graft with HLA-A,-B mismatches. The alloantibodies were detected by a complement-dependent cytotoxicity (CDC) technique and an ELISA method in parallel; they were classified as HLA graft-specific (GS) and non-GS antibodies. The aa triplet specificity of the antibodies was assessed using the HLAMatchmaker algorithm. HLA class I antibodies were detected in 74 of 78 (94%) cases, including GS reactivity in 55 (74.3%) and non-GS in 72 (97.2%), either alone (n = 19) or in parallel with GS antibodies (n = 53). For all HLA-GS-antibody-reactive patients, we defined the specificity against immunogenic aa triplets on the previous graft. Moreover, antibodies specific to graft aa triplets were observed within the non-GS antibodies among 19 of 19 and 28 of 53 cases, respectively. Therefore, aa triplet-specific antibodies against the rejected graft were present in all 74 cases with HLA class I antibodies. Antibodies against aa triplets expressed on all HLA class I-mismatched graft antigens were present in 73% of cases. The high extent of humoral alloreactivity against a rejected graft supports the decision to avoid repeated exposure to immunogenic aa triplet mismatches on a second graft. An accurate analysis for performed antibodies in these cases may be beneficial to select the most suitable second donor.