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Non-hla Specific Antibodies in Lung Transplantation, Binding and Mechanisms of Injury: Clinical Relevance

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Introduction

Lung transplantation is the most recognized treatment for advanced stage lung disease. Since 1990s more than 62000 lung transplants have been completed worldwide (ISHT data). Recent data on single-lung transplants show that 78% patients survive the first year and 51% of patients survive 5 years (NIH). Lung transplant patients have significantly less survival when compared to other solid organ transplants, including kidney and heart transplants which have 85% and 75% survival after 5 years, respectively. The less survival rate among lung transplant patients can be attributed to the rejection via development of airflow obstruction known as BOS. Different interventional approaches are being researched upon to recognize the patients who are at high risk for developing BOS to enhance the outcomes. Several risk factors for the development of BOS have been elucidated which can be alloimmune-dependent and -independent. Viral infections, gastroesophageal reflux, primary graft dysfunction, are known to be associated with BOS initiation.

The allo and auto immunity are known to be possibly connected to each other and further to chronic rejection. The development of immune responses to self-antigens and its possible role in the pathogenesis of chronic rejection (BOS) following human LTx has been reported recently both by our group and others. Following human LTx several immune mediated and non-immune mediated risk factors donor and recipient age, graft ischaemic time, gastro-oesophageal reflux disease (GERD), metalloproteinase degradation and bacterial/fungal/non-cytomegalovirus (CMV) viral infection] have been associated with development of inflammatory milieu within the graft. Administration of Abs to lung associated self-Ags can lead to both cellular and humoral immune responses. It has recently been shown that T cells specific for lung tissue-restricted sAgs are not deleted by the thymus, but are actively suppressed by thymically derived, antigen-specific forkhead box P3 (Foxp3)1 regulatory T cells (Tregs). Loss of Tregs, for example, by respiratory viral infections, can lead to the expansion of lung tissue–restricted T cells and development of both cellular and humoral lung-restricted autoimmunity. This area is still a relatively unknown, but it is reasonable to expect that further investigations will allow the prevention of posttransplant immune complication. This review is to show the importance of non-HLA specific antibodies. Strategies to detect and deplete such Abs during post-transplant may represent a novel approach to prevent BOS following human LTx.

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Allo immunity: The alloimmunity acts by producing antibodies through direct or indirect recognition. In direct recognition pathway the recipient T cells identify the donor antigens directly displayed by histocompatibility complex on their surface as the peptide complexes. Recipient antigen processing cells (APC) are not needed in the direct pathway and is based on the higher affinity of allorecognition by T cells for alloantigens as compared to the other antigens. This pathway is major in responses leading to acute rejection. It was demonstrated that dendritic cells primarily elicit the direct pathway via diminishing the donor dendritic cells which led to immunogenicity failure which was normalized after addition of these cells. In a study conducted by Lakkis et al. (2000) depicted that immune response in the transplanted graft cannot be induced in absence of secondary lymphoid tissue. Indirect antigen presentation is important in chronic rejection and allows when the processed antigen of donor origin is presented to recipient T cells by APC. In certain circumstances, the indirect pathway independent of direct pathway leads to a swift acute graft rejection. There is some evidence for another pathway called the semi-direct, such as in the study where cells lacking APC were rejected even in the absence of the indirect recognition.

Further, recipient without MHC class II or indirect recognition mechanism were able to reject the allogeneic grafts. Semi-direct pathway was debated to be three-cell linked or four-cell unlinked model initially. In the Three cell model proposed that CD4+ and CD8+ T cell interactions are activated by same APCs to produce an immune response. Further, CD4+ T cells activated through the indirect mechanism might be involved in either augmentation or normalization of allo-specific CD8+ T cells. The contrasting idea of a four-cell/unlinked model believed that the CD8+ cells and CD4+ T cells are stimulated by donor and recipient APCs, respectively. It was found that dendritic cells can acquire MHC-antigen complex from similar dendritic or endothelial cells to display them to allo-reactive T cells. It can be concluded that in the semi-direct recognition pathway recipient APCs uptake the MHC antigen complex by either direct cell-to-cell contact or through exosomes, along with activating the direct pathway CD8+ T cells.

Autoantibodies: Primary graft dysfunction (PGD) along with Ob is the major cause of early mortality in patient s after the transplant. The emerging role of de novo and preexisting autoantibodies in lung transplant in PGD is being evaluated. Our group recently reported that lung restricted auto antibodies collagen (Col) type V and K-α1 tubulin (KAT) are involved in mediation of rejection after lung transplant. Lung self-antigens are normally deleted in the thymus. Sags which escape thymic deletion are suppressed by T resulatory cells and are present in sequestered form CD4+CD25+Foxp3+ regulatory T-cells (Tregs). Lung self antigens such as Colv and k tub are known to be intracellular and are not normally detected in the lungs. Col (V) is also expressed on epithelial cells in the lungs which makes it readily susceptible to humoral and cellular responses. In Lung ischemia reperfusion injury after the transplant the matrix metallosproteins unmasks the col v by cleaving it which coincides with its detection in between 4 hours of tranplanst upto 30 days.

It is believed that these self-antigens are transported in the form of blebs to the surface during apoptosis which is a usual attribute to lung injury after transplant swhich then leads to auto immunity. It is well recognized that T cells play and important role towards distinguishing self and non-self. Activated CD4+ T cells are known to differentiate into either Th1, Th2 or Th17 phenotypes, characterized by production of specific cytokines. It is of interest to note that polarization of the T cells into Th phenotypes is often mutually antagonistic and Th2 inhibits the differentiation of Th1 and Th17sTregs are found in many different tissues and are significant in both auto and allotolerance by suppressing inflammation and autoimmune response Since, LTx patients undergo several repeated injury and repair processes, this might lead to expansion of Se;f Ags which might be due to sequestered Sags, epitope spreading and reduction of activation thresholds. Most LTx recipients develop de novo antibodies in less than 3 years after the tyransplant. IL-17 production as a response to SAgs is important in chronic rejection since its neutralization prevented the OB. Moreover, blocking of Th17 cells Th17 prevents OAD.

Regulatory circuit’s including Treg cells impact the advancement of autoimmunity in lung transplant recipient and are necessary to prompt antibodies against antigens in formerly injured lungs. The mechanism of OB by SAgs to produce autoantibodieas and their resultant signaling pathways are required to be considered for therapeutic intervention to protect the lung graft before permanent antibody mediated damage occurs. Linking auto and allo immunity: The presence of humoral immunity in allo graft rejection is already knwoon. Airway epithelial cells are one of the important targets in lung graft rejection. Anti-MHC class I molecules stimulate airway obliteration by the release of various fibriogenic factors such as, basic fibroblast growth factor (b- FGF), granulocyte monocyte colony-stimulating factor and transforming growth factor-beta (TGF-beta).

In a study we found that administering anti MHC I Ab to different mice strain induced epithelial hyperplasia and fibrosis. Moreover, IL-17 levels increased wchich further induced Tcells against self Ags including K-alpha1T and col V. Denovo autoantibodies against these self Ags were also recorded. IL-17 seems to be promote the generation of auto-Abs. In another study, we demonstrated that in lung transplant patients binding of the self Ag anti-K-α1 tubulin to the epithelial cells increased expression of transcription factor, TCF5, mediating inflammatory response genes. Also, TCF5 possibly affects the fibro-proliferation cascade which is leads to BOS subsequent to the lung transplantation. The Kα1T Abs also increase expression of hypoxia inducible factor (HIF-1α) and inhibition of the HIFa normalized the fibriotic growth factor levels. It is suggested that induction of Ka1 Ab are involved in the upregulation of HIF a mediated firogenesis after the ;umg TX. Autoimmunity prior to transplantation: It is well-known that in most cases after the lung transplant the grafts develop primary graft dysfunction. PGD develops within first 2 days of the transplant and eventually can possibly lead to BOS since suggested by previous studies it is known that patients with PGD are at two and a half times higher.

Several studies have shown the evidenc of pre-existing auto antibodies. Bobadilla et al also found that about 58% of patients with idiopathic pulmonary fibrosis and 16% of patients without idiopathic pulmonary fibrosis have anti-collagen V immunity detected by using the trans-vivo mouse footpad delayed type hypersensitivity model. When lung transplant patients were assessed for the presence of autoauntibodies, 28% were found to have at a minimum of one AutoAb against the self Ags which included col I, colv and k a tubulin. The incidence of PGD increased with the type of autoab. Donor specific antibodies can be directed against differentclasses of HLA and non HLA antigens which are expressed on epithelial, endothelial cells. Howvever, there is a variation in incidence of de novo DSA after the transplant as noted by Hachem et al that 56% patients developing DSA compared to Lobo et al. who detected 29. 5% DSA development in 557 days after transplantation. De novo post-transplant antibodies: We found that lung transplant recipients are predisposed to the development of de novo Abs following respiratory viral infections.

In summary, we have shown that lung recipients with strong/intermediate binding antibodies to AT1R and ETAR have lower freedom from AMR and ACR. When pre- transplant sera contained HLA-specific antibody together with strong binding antibody to either AT1R or ETAR, an increased negative impact on the freedom from develop- ment of de novo DSA was observed. These results provide insight into the processes leading to rejection events involving both the auto and alloimmune responses. Importantly, pretrans- plant assessment of HLA specific and non–HLA-specific antibody status allows for the immunological risk stratifi- cation of lung recipients potentially leading to strategies for clinical intervention.

Mechanisms/pathways for non-HLA mediated lung graft rejection: Various mechanisms including molecular mimicry and bystander activation release of the sequestered self-Ags, lowering of activation thresholds of self-reactive lymphocytes, and epitope spreading. C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody Complement activation is a common feature of autoantibody-induced tissue injury and pathology. Indeed, we reported that anti-col(V) antibody induced injury to airway epithelial cells was complement dependent. However, autoantibodies can induce apoptosis in target cells in the absence of complement activation. Alternatively, antibodies may mediate antibody dependent cellular cytotoxicity (ADCC) by macrophages or NK cells recognition of autoantibodies bound to their respective autoantigens. While ADDC is a putative mechanism, it has not been reported to be associated with autoantibody induced injury post lung transplantation. Autoantibodies could also induce tissue injury by induction of signaling cascades within cells expressing the autoantigens. For example, Goers reported that binding of K-α1 tubulin antibodies to airway epithelial cells induced strong expression of signaling proteins such as protein kinase-C (PKC), as well as vascular endothelical growth factor, TGF-β, and heparin binding epidermal growth factor-like growth factor (12). Although not all of these have been implicated in lung allograft pathology, TGF-β is likely to have key roles in fibrogenesis that is characteristic of OB.

Clearly, more studies are needed to reveal the mechanism of role of autoantibody-induce pathology post lung transplantation.

Anti-airway epithelial cell antibodies isolated from patients induce intracellular calcium increase, proliferation, and tyrosine phosphorylation in airway epithelium.

Agonistic stimulation of HLA I, HLA II, endothelial or epithelial cell surface markers may induce intracellular signaling leading to recruitment of immune cells, apoptosis, survival or proliferation. Thus, alloantibody can elicit complement deposition and neutrophil infiltration, features of acute rejection, as well as cellular proliferation and vascular lesion formation, characteristic of chronic rejection.

Th17 cells specific to self-Ags play an important role in development of self-Ags specific immune responses. Blocking of Th17 can prevent rejection.

IFN-γ and IL-17 responses in development of self-Ag* Proposed that once Abs are bound to one of the self-Ags, it leads to opsonization of the membrane by Ag presenting cells leading to further activation, phenotypic switch leading to immune response to all the antigens present on the phagocytized membrane leading to spreading of immune responses to other self-Ags, and likely to alloantigen’s in allografts.

Ligands for non-HLA antibodies:

Collagen type I & collagen type V: Antibodies against Col-I, Col-V and Kα1T were detected in 18 to 34% of patient’s pre-transplantation depending on their baseline lung disease, compared to only 3% of normal volunteers. The presence of these antibodies pre-transplantation significantly increased the odds of primary graft dysfunction by 7 and of BOS by 20. Collagen V is present on airway epithelial cells and its expression increases following immune-mediated injury and/or IRI74.

K-alpha-1 tubulin: Kα1 tubulin (Kα1T) is a gap junction protein. HIF-1α -mediated upregulation of fibrogenic growth factors induced by ligation of Kα1T Abs is critical for development of fibrosis leading to chronic rejection of lung allograft.

Endothelial antigenic targets: Antibodies to GPCRs: Angiotensin-II type 1 receptor (AT1R) and endothelin type A receptor (ETAR)A recent report in lung transplant recipients also indicates worse allograft outcomes when antibodies to both HLA and either AT1R or ETAR are present. Pre and posttransplant sera from 162 lung recipients transplanted at 3 different centers showed a lower freedom from de novo DSA when the pretransplant antibody status of HLA specific antibodies (HR=1. 69) together with either antibodies to AT1R (HR2. 26) or ETAR (HR=2. 38) in the strong binding range were considered. Lower freedom from CMR was observed for recipients with intermediate or strong levels of antibody to AT1R and ETAR. Although antibodies against AT1R and ETAR have been shown to be of the IgG1 and IgG3 subclasses, biopsies of AT1R antibody positive patients with graft dysfunction are frequently of the C4d negative rejection phenotype. Thus, the mode of graft destruction does not appear to be limited to complement-mediated injury but likely includes mechanisms of endothelial damage distinct to non-HLA antibodies which appear to synergize with HLA specific antibodies. Vimentin: Vimentin, which is only found in mesenchymal cells, is a kind of intermediate filament protein, attached to nucleus, endoplasmic reticulum, and the sides or end of mitochondrion, making great contribution to support and anchor organelles in the protoplasm and playing an important role in the cell shape maintenance. Vimentin expression in transplanted lungs compared to normal lung tissues, which means an EMT process happened.

One study of patients with non–small-cell lung cancer showed that expression of vimentin and E-cadherin correlated with favourable patient outcome for erlotinib treatment, which suggested that vimentin has a role as a predictive biomarker for this therapy(Danielsson et al. 2018) Vimentin has also been shown to regulate a wide spectrum of basic cellular functions. In cells, vimentin assembles into a network of filaments that spans the cytoplasm. It can also be found in smaller, non-filamentous forms that can localise both within cells and within the extracellular microenvironment. The vimentin structure can be altered by subunit exchange, cleavage into different sizes, re-annealing, post-translational modifications and interacting proteins. Together with the observation that different domains of vimentin might have evolved under different selection pressures that defined distinct biological functions for different parts of the protein, the many diverse variants of vimentin might be the cause of its functional diversity.

The importance of self antigenss, K-α tubulin and collagen V in lung allograft rejection is already implicated. A study was conducted by (Reinsmoen et al. 2015) to establish the role of other self-antigens, including perlecan (LG3 fragment), vimentin, and fibronectin leucine rich transmembrane protein (FLRT2) in lung transplant rejection. In the sera of lung transplant recipients after the transplant the ab binding to above mentioned autoantigens increased.

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