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Causes and risk factors
Published in Janetta Bensouilah, Pregnancy Loss, 2021
Despite advances in understanding of the immunological disruption to pregnancy that can occur in some women, and the availability of treatments that might address some of these conditions, the precise role of the immune system in pregnancy loss remains uncertain. For a pregnancy to be successful, complex adaptations in the immune response need to occur so that the maternal reaction to the embryo, which is essentially 50% foreign tissue, is life-sustaining rather than lethal. Whereas pregnancy was once viewed as a conflict between fetus and maternal immunity, a conceptual reframing has been taking place, and the many cooperative interactions between the two are now emphasised in reproductive immunology.15 When responses go awry, two immunological mechanisms are involved, namely those involving autoimmune factors and alloimmunity.
Opinion: Immunotherapy Has No Place in the Treatment of Recurrent Pregnancy Loss*
Published in Howard J.A. Carp, Recurrent Pregnancy Loss, 2020
Regardless, immunotherapy has been introduced into clinical practice as a treatment for RM based on the hypotheses that either alloimmunity or autoimmunity is responsible for pregnancy failure. In order to critically evaluate the use of paternal or third-party white cell immunization (active immunization), intravenous immunoglobulin (passive immunization), or cytokine modulation as treatment for RM it is necessary to examine the rationale for their use, and the results that are currently available.
Graft versus host disease
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Sandeep Arora, Sandeep Lal, Manasa Shettisara Janney
Chronic GVHD is the most common cause of death in late nonrelapse mortality in hematopoietic stem cell transplant (HSCT) and affects the quality of life adversely. The exact pathophysiology involved in the clinical manifestations of cGVHD is still obscure. However, the concepts of autoimmunity and alloimmunity are widely accepted. The impaired negative selection of the T cells in host's thymus (compromised by conditioning regimens) and escape of these T cells from the peripheral tolerance mechanism are implicated in the proliferation of auto- and alloreactive cells. These T cells are directed against the self-antigens causing autoantibody production, which explains the high incidence of autoantibodies detected in cGVHD [18]. Another model proposes that the donor T cells are chronically activated by the heterogenous host antigens. The success of rituximab (an anti-CD20 antibody) in treatment of GVHD suggests the role of B-cell-mediated autoimmunity in GVHD [19].
Emerging drugs for antibody-mediated rejection after kidney transplantation: a focus on phase II & III trials
Published in Expert Opinion on Emerging Drugs, 2022
Katharina A. Mayer, Klemens Budde, Bernd Jilma, Konstantin Doberer, Georg A. Böhmig
At present, there is limited formal evidence for the efficacy of the available repertoire of ABMR treatment (SOC) [11,22]. Thus, there is a need for adequately powered trials that prove the benefits and risks of specific treatment strategies. Given the fact that ABMR is a cardinal cause of graft failure [1–6], accomplishing the goal of an effective treatment would potentially improve overall transplant outcomes. This would also be beneficial for other organs as well as for other types of transplantation (e.g. xenotransplantation), where humoral alloimmunity is known to play a pivotal role. However, the development of new therapies to improve clinically relevant outcomes (patient and graft survival; safety; quality of life) in patients diagnosed with ABMR will be a lengthy process, because overall ABMR is a rare condition. Thus, effective prevention of ABMR remains an important goal in transplantation.
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].
Development of transplant immunosuppressive agents – considerations in the use of animal models
Published in Expert Opinion on Drug Discovery, 2018
Russell Costello, Adrien Kissenpfennig, Paulo N Martins, James McDaid
Alloimmunity in transplants is unique in that it involves direct, indirect and semi-direct recognition. Indirect recognition conforms to classical immunology dogma, and occurs where helper T cells recognize fragments of major histocompatibility complex (MHC) from the donor’s cells, presented by host antigen presenting cells (APC). This is similar to the process of autoimmunity. Direct recognition involves host T cells being directly activated by donor APCs [2]. This is believed to be the main pathway in generating an early alloimmune response after transplantation [1]. Semidirect allorecognition [2] occurs when direct pathway T cells recognize intact allo-MHC which has been transferred from the surface of donor APCs onto recipient APCs [3,4]. Chimeric host APCs, which have been transferred intact donor MHC through cell-to-cell contact or exosomes, may directly present intact donor MHC during semi-direct responses. Treatment for both auto-immunity and alloimmunity is similar, involving drugs and biologic agents, which dampen the innate and adaptive responses [5]. Most drugs target T cell activation, through inhibition of intracellular signaling molecules. However, others such as mycophenolate can target the maturation and function of dendritic cells which act as APCs, as well as preventing purine synthesis necessary for lymphocyte proliferation [6]. This provides efficacy against both autoimmunity and direct/indirect/semi-direct alloimmunity. Steroids target both cells of the innate and adaptive immune system, with effects on antigen presenting cells, T cells and B cells. A number of so-called ‘biologic agent’ strategies have been developed in recent years. An example is Rituximab, a monoclonal antibody targeting CD20, which leads to B cell depletion. It is used in ABO blood group incompatible transplantation [7].We cover these and other commonly utilized immunosuppressive strategies in this review (Table 1).