Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment.

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.

Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.

The Body in Pain: What do people of faith have to say about torture

An examination of why American Protestant churches have a higher likelihood to support torture

Peculiar Motion

A collection of poetry

Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4-Ig.

Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor-specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4(+) CD25(+) FoxP3(+) T reg cell numbers during treatment. On the contrary, ICOS(+) PD-1(+) CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4-Ig supplementation in conjunction with rapamycin corrected rapamycin-induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4-Ig.

Internal carotid arterial canal size and scaling in Euarchonta: Re-assessing implications for arterial patency and phylogenetic relationships in early fossil primates.

Primate species typically differ from other mammals in having bony canals that enclose the branches of the internal carotid artery (ICA) as they pass through the middle ear. The presence and relative size of these canals varies among major primate clades. As a result, differences in the anatomy of the canals for the promontorial and stapedial branches of the ICA have been cited as evidence of either haplorhine or strepsirrhine affinities among otherwise enigmatic early fossil euprimates. Here we use micro X-ray computed tomography to compile the largest quantitative dataset on ICA canal sizes. The data suggest greater variation of the ICA canals within some groups than has been previously appreciated. For example, Lepilemur and Avahi differ from most other lemuriforms in having a larger promontorial canal than stapedial canal. Furthermore, various lemurids are intraspecifically variable in relative canal size, with the promontorial canal being larger than the stapedial canal in some individuals but not others. In species where the promontorial artery supplies the brain with blood, the size of the promontorial canal is significantly correlated with endocranial volume (ECV). Among species with alternate routes of encephalic blood supply, the promontorial canal is highly reduced relative to ECV, and correlated with both ECV and cranium size. Ancestral state reconstructions incorporating data from fossils suggest that the last common ancestor of living primates had promontorial and stapedial canals that were similar to each other in size and large relative to ECV. We conclude that the plesiomorphic condition for crown primates is to have a patent promontorial artery supplying the brain and a patent stapedial artery for various non-encephalic structures. This inferred ancestral condition is exhibited by treeshrews and most early fossil euprimates, while extant primates exhibit reduction in one canal or another. The only early fossils deviating from this plesiomorphic condition are Adapis parisiensis with a reduced promontorial canal, and Rooneyia and Mahgarita with reduced stapedial canals.