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Suppressor Cell Activity in Human Cord Blood
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Nikos Papadogiannakis, Svend-Aage Johnsen, Lars B. Olding
Suppressor T-cells (Ts), first demonstrated by Gershon and Kondo in the phenomenon of “infectious tolerance”,1 form a distinct regulatory system. They can inhibit diverse aspects of humoral and cell-mediated immunity, and their role has been investigated in such areas as unresponsiveness and tolerance, malignancy, and various disease states. T-cell suppression can be antigen-specific or nonspecific and may be mediated by antigen or idiotypic determinants.2,3
Future therapies in lung transplantation
Published in Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell, LUNG Transplantation, 2016
Elizabeth A. Lendermon, John F. McDyer
CD154 (CD40L) is a protein that belongs to the tumor necrosis factor (TNF) superfamily and is expressed on the surface of activated CD4+ T cells. It binds to CD40 on APCs to effect activation in these cells, as well as on B cells, in which case binding is necessary for immunoglobulin class switching. In addition, interaction between CD154 and CD40 has been shown to be important for the development of the type 1 helper T-cell (Th1) responses14,15 that are critical in transplant rejection. In multiple experimental transplant models (both rodents and nonhuman primates), blockade of the CD154-CD40 pathway via use of a monoclonal antibody (mAb) against CD154 at the time of transplantation has been shown to result in improved allograft acceptance.16–19 Multiple mechanisms of anti-CD154-induced allograft acceptance appear to exist. Early animal studies examining anti-CD154 in combination with CTLA4Ig revealed an important role for activation-induced cell death.20,21 Subsequent studies demonstrated that anti-CD154 therapy provided an infectious tolerance that is now attributable to regulatory T cells.22–24 In a mouse orthotopic transplant model, use of anti-CD154 alone at the time of transplantation resulted in abrogation of allospecific CD4+ and CD8+ effector cytokine responses, a massive increase in the population of regulatory T cells in the allograft, and improved allograft acceptance.25 Therefore, it is clear that anti-CD154 therapy has many desirable tolerogenic effects in animal models.
Regulatory T cells as therapeutic targets and mediators
Published in International Reviews of Immunology, 2019
Both autoimmunity and alloimmunity have long been clinically managed by general immunosuppression. With the efforts to utilize Tregs for these therapies, a specificity is being brought, which can protect against the ills of a global suppressive milieu. However, Treg therapy is in its infancy and several issues are still being addressed. For the adoptive Treg therapy, the process of manufacturing of Tregs is itself tricky. We still do not have markers which can be utilized for identifying Tregs with absolute surety. Also, a cell therapy requires Good Manufacturing Practice (GMP) manufacturing facilities which are scarce and costly. The rather non-feasibility of imparting these treatments outside research facilities is also a major hurdle. The individual nature of cell therapy is a deterrent but is safe. This is being addressed by off-the-self ‘universal Tregs’ [173]. To suppress alloimmunity and establish an immune tolerance, the number of adoptively transferred Tregs is very high (and not yet totally defined), so better strategies for ex vivo expansion of Tregs and clinical studies looking at safety of transferred Tregs in the efficacy ranges of Tregs are a requisite. The ex vivo hyper-expansion strategies with artificial APCs need to be pursued as well [174]. Also, better understanding of mechanisms of Treg mediated ‘infectious tolerance’ can supplement this endeavor [175].
Role of extracellular vesicles in severe pneumonia and sepsis
Published in Expert Opinion on Biological Therapy, 2022
Wonjung Hwang, Masaru Shimizu, Jae-Woo Lee
As suggested by the immunosuppressive properties of EVs released from multiple stem and progenitor cells, not all EVs released into the plasma during bacterial pneumonia and/or sepsis are inflammatory. Many EVs may be immunomodulatory as well, especially during the different phases of the syndrome. For example, activated and recruited macrophages (M1) are critical for the exudative phase of ARDS where the cells are primarily inflammatory whereas similar macrophages are shifted to the (M2) phenotype during the proliferative phase and are involved eliminating apoptotic cells and participating in fibrosis[157]. Multiple laboratories have demonstrated that EVs released by stimulated or activated endothelial cells or macrophages in vitro or EVs released into the plasma in LPS injured rats can induce ALI when administered into naïve animals whether through intra-tracheal or intravenous routes[53,61,65]. Whereas Yang et al. found that EVs isolated from M2 macrophages (subtype b) significantly attenuated the severity of DSS-induced colitis in mice which was associated with increased regulatory T (Treg) cells in the spleens and levels of IL-4[158]. Similar to the role of Treg cells in the maintenance of immune tolerance against self and foreign antigens through the control of harmful inflammation, investigators have also speculated that EVs released by Treg cells may contribute to infectious tolerance by intervening with CD4+ T cells differentiation and/or stability[159]. In the proliferative phase of ARDS, regulatory T-cells promote pulmonary repair by modulating T helper cell immune responses[160]. Thus, targeting all EVs to suppress the ‘cytokine storm’ associated with ARDS or septic shock may be appealing but may not be successful[161], similar to the largely equivocal or negative results from previous clinical trials using anti-inflammatory drugs (i.e. corticosteroids) in ARDS[162] and anti-TNF in sepsis shock[163,164]. Regardless, one definite conclusion that can be drawn from these studies is that the timing of sample collection for analyses for EV content is critical for correctly characterizing the phenotype of these EVs. One wonders about the phenotype of the EVs in the study by Guervilly et al. that found that higher levels of LEVs in the blood and BALF were associated with improved survival in patients with early-stage ARDS[63].