The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with ...alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.
Transplantation is a life-saving therapy for end-stage organ disease, yet the alloreactive T cell response poses a significant barrier to long-term graft survival. Seminal studies and emerging findings have defined the roles that T cell costimulatory and coinhibitory receptors play in tipping the balance between transplant rejection and tolerance.
Background
Simultaneous inactivation of pig GGTA1 and CMAH genes eliminates carbohydrate xenoantigens recognized by human antibodies. The β4GalNT2 glycosyltransferase may also synthesize ...xenoantigens. To further characterize glycan‐based species incompatibilities, we examined human and non‐human primate antibody binding to cells derived from genetically modified pigs lacking these carbohydrate‐modifying genes.
Methods
The Cas9 endonuclease and gRNA were used to create pigs lacking GGTA1, GGTA1/CMAH, or GGTA1/CMAH/β4GalNT2 genes. Peripheral blood mononuclear cells were isolated from these animals and examined for binding to IgM and IgG from humans, rhesus macaques, and baboons.
Results
Cells from GGTA1/CMAH/β4GalNT2 deficient pigs exhibited reduced human IgM and IgG binding compared to cells lacking both GGTA1 and CMAH. Non‐human primate antibody reactivity with cells from the various pigs exhibited a slightly different pattern of reactivity than that seen in humans. Simultaneous inactivation of the GGTA1 and CMAH genes increased non‐human primate antibody binding compared to cells lacking either GGTA1 only or to those deficient in GGTA1/CMAH/β4GalNT2.
Conclusions
Inactivation of the β4GalNT2 gene reduces human and non‐human primate antibody binding resulting in diminished porcine xenoantigenicity. The increased humoral immunity of non‐human primates toward GGTA1‐/CMAH‐deficient cells compared to pigs lacking either GGTA1 or GGTA1/CMAH/β4GalNT2 highlights the complexities of carbohydrate xenoantigens and suggests potential limitations of the non‐human primate model for examining some genetic modifications. The progressive reduction of swine xenoantigens recognized by human immunoglobulin through inactivation of pig GGTA1/CMAH/β4GalNT2 genes demonstrates that the antibody barrier to xenotransplantation can be minimized by genetic engineering.
Memory T cells that are specific for alloantigen can arise from a variety of stimuli, ranging from direct allogeneic sensitization from prior transplantation, blood transfusion, or pregnancy to the ...elicitation of pathogen-specific T cells that are cross-reactive with alloantigen. Regardless of the mechanism by which they arise, alloreactive memory T cells possess key metabolic, phenotypic, and functional properties that render them distinct from naive T cells. These properties affect the immune response to transplantation in 2 important ways: first, they can alter the speed, location, and effector mechanisms with which alloreactive T cells mediate allograft rejection, and second, they can alter T-cell susceptibility to immunosuppression. In this review, we discuss recent developments in understanding these properties of memory T cells and their implications for transplantation.
The intestinal microenvironment in sepsis Fay, Katherine T.; Ford, Mandy L.; Coopersmith, Craig M.
Biochimica et biophysica acta. Molecular basis of disease,
10/2017, Volume:
1863, Issue:
10
Journal Article
Peer reviewed
Open access
The gastrointestinal tract has long been hypothesized to function as “the motor” of multiple organ dysfunction syndrome. The gastrointestinal microenvironment is comprised of a single cell layer ...epithelia, a local immune system, and the microbiome. These three components of the intestine together play a crucial role in maintaining homeostasis during times of health. However, the gastrointestinal microenvironment is perturbed during sepsis, resulting in pathologic changes that drive both local and distant injury. In this review, we seek to characterize the relationship between the epithelium, gastrointestinal lymphocytes, and commensal bacteria during basal and pathologic conditions and how the intestinal microenvironment may be targeted for therapeutic gain in septic patients.
•The epithelium, local immune system, and intestinal microbiome are interconnected and essential to maintaining host health.•Sepsis alters the intestinal microenvironment, promoting epithelial cell barrier breakdown, inflammation, and domination of pathogenic bacteria.•TPN and other modifications in nutrition affect epithelial integrity, immunological function, and bacterial pathogenesis.•Re-establishing a homeostatic intestinal microenvironment may be a useful treatment approach to sepsis.
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of ...costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology. Abatacept and belatacept are clinically approved agents for the treatment of rheumatoid arthritis and renal transplantation, respectively. Future interventions may include selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4.
Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there ...are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis induce a significant increase in intestinal permeability mediated through a common pathway involving alterations in claudin 2, claudin 5, JAM-A, and occludin although model-specific differences in ZO-1 were also identified.
Defining pathways that differentially regulate graft-reactive versus anti-microbial T cell responses could facilitate more precise manipulation of immune responses in the context of organ and tissue ...transplantation. Here, Jayachandran et al. (2019) identify a coronin-1-PDE4-cAMP axis that, when perturbed, results in the induction of transplantation tolerance while maintaining anti-microbial immunity.
Defining pathways that differentially regulate graft-reactive versus anti-microbial T cell responses could facilitate more precise manipulation of immune responses in the context of organ and tissue transplantation. Here, Jayachandran et al. (2019) identify a coronin-1-PDE4-cAMP axis that, when perturbed, results in the induction of transplantation tolerance while maintaining anti-microbial immunity.
Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term ...graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens - through direct, indirect or semi-direct pathways - will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance.
In this editorial, Ford discusses how the report by Zou et al (page 2540) dissects the relationship between antigen exposure, Tox expression, and tolerance induction during transplantation.
Antagonism of the CD154/CD40 pathway is a highly effective means of inducing long‐term graft survival in preclinical models. Using a fully allogeneic murine transplant model, we found that CD154 ...blockade was more effective in prolonging graft survival than was CD40 blockade, raising the possibility that CD154 binds a second receptor. To test this, we queried the impact of CD154 antagonism in the absence of CD40. Data indicated that anti‐CD154 functioned to reduce graft‐infiltrating CD8+ T cells in both WT and CD40−/− hosts. Because it has recently been reported that CD154 can ligate CD11b, we addressed the impact of blocking CD154‐CD11b interactions during transplantation. We utilized a specific peptide antagonist that prevents CD154 binding of CD11b but has no effect on CD154‐CD40 interactions. CD154:CD11b antagonism significantly increased the efficacy of anti‐CD40 in prolonging allograft survival as compared to anti‐CD40 plus control peptide. Mechanistically, CD154:CD11b antagonism functioned to reduce the frequency of graft‐infiltrating CD8+ T cells and innate immune cells. These data therefore demonstrate that blocking CD154 interactions with both CD40 and CD11b is required for optimal inhibition of alloimmunity and provide an explanation for why CD40 blockers may be less efficacious than anti‐CD154 reagents for the inhibition of allograft rejection.
CD154‐CD11b interactions promote CD8+ T cell migration into allografts even when CD40 is blocked, providing a mechanistic basis for why CD154 blockade may be functionally superior to CD40 blockade in preventing alloimmunity and graft rejection.
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