Graft versus host disease
Biju Vasudevan, Rajesh Verma in Dermatological Emergencies, 2019
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].
Causes and risk factors
Janetta Bensouilah in 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.
Immunology of lung transplantation
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
One hypothesis for why autoimmunity and alloimmunity cannot be as easily suppressed once initiated is that Tregs are decreased in number, absent, or dysfunctional following transplantation.47 Additionally, calcineurin inhibition, a key component of most recipient immunosuppression regimens, has been shown to abrogate Treg function.87 A correlation between decreased number of Tregs and the incidence of BOS in lung transplant recipients has been reported.88 Furthermore, Bharat and colleagues found that T-cell lines reactive to col(V) isolated from lung transplant recipients produced IL-10 and are capable of suppressing proliferation and IFN-γ secretion from autoreactive T cells.89 However, patients in whom BOS developed had a decline in the frequency of IL-10–producing T-cell clones.89 These data suggest that lung transplant recipients may be able to lessen the autoimmune response to col(V) through either natural Tregs or adaptive Tregs.90 Interestingly, a recent study provided evidence that alveolar epithelial cells may induce Tregs specific for endogenous lung antigens during inflammation, thus suggesting that lung epithelium is a major regulator of induced Tregs.91 The normal homeostasis of the lung may be undermined by immunosuppression and alloimmunity. Strategies to promote immune tolerance to alloantigens, autoantigens such as col(V), or yet-to-be-identified antigens in lung transplantation hold promise to prevent the devastating complication of CLAD.
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].
An update on current treatment strategies for managing bronchiolitis obliterans syndrome after lung transplantation
Published in Expert Review of Respiratory Medicine, 2021
Ashwini Arjuna, Michael T. Olson, Rajat Walia, Ross M. Bremner, Michael A. Smith, Thalachallour Mohanakumar
During and after LTx, the donor lungs are subjected to injuries that increase the antigenicity of the transplanted organ. Our laboratory has focused on studying these injuries and their role in the development of inflammatory mediators that predispose chronic rejection. While alloimmunity directed against donor HLA has been implicated in rejection, lung-restricted autoimmunity has emerged as potentially the final common terminal pathway leading to chronic rejection from a variety of risk factors that promote donor lung insult. Repeated cycles of injury and repair in LTxRs exposed to these risk factors may even expand lung-restricted autoimmunity. For these reasons, the studies which we have published in the last year implicating ischemia-reperfusion (i.e., primary graft dysfunction), gastroesophageal reflux, microbial infection, and stress-induced exosome release [31,93–95] may supply even more evidence toward the importance of mitigating the risk of allograft injury. We have since conducted proteomic analyses that revealed protein signatures in circulating extracellular vesicles that uniquely belong to LTxRs with acute rejection, BOS, and respiratory viral infection, offering new insight into the immunological mechanisms of allograft rejection [96].
Donor-specific antibodies following liver and intestinal transplantation: Clinical significance, pathogenesis and recommendations
Published in International Reviews of Immunology, 2019
Laura J. Wozniak, Robert S. Venick
Non-HLA antibodies are known to play an important role in other fields of solid organ transplantation. Their role in LTx is largely undefined but appears to be associated with fibrosis. In pediatric LTx recipients, angiotensin II type 1 receptor (AT1R) antibodies were found by Ohe et al. [27] to be significantly more common in patients with graft fibrosis after immunosuppression withdrawal. Similarly, in adult LTx recipients, the presence of non-HLA (AT1R and endothelin-1 type A receptor) antibodies and pre-formed HLA DSA was associated with fibrosis progression on one-year post-transplant biopsies in a study by O’Leary et al. [32]. It remains unclear as to whether HLA DSA develop before or after non-HLA antibodies; autoantibodies may be triggered by alloimmunity, and autoimmunity may trigger alloantibodies. Regardless, allo- and auto-antibodies may work synergistically in graft damage and rejection [49]. Further clinical and mechanistic studies of non-HLA antibodies are needed and may aid in the development of effective medical therapy for chronic AMR.
Related Knowledge Centers
- Allotransplantation
- Antibody
- Blood Transfusion
- Fetus
- Histocompatibility
- Immune System
- Antigen
- Species
- Blood Type
- Transplant Rejection