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

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Published: 3rd Feb 2022

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Most end stage lung disease patients require lung transplantation though it has the lowest survival rate among other solid organ transplants. The lung-restricted self-antigens include collagen type I, collagen type V, and k-alpha 1 tubulin. In this review, we discuss the role of lung-restricted autoimmunity in the development of both early as well as late lung allograft rejection and recent literature providing insight into the development of lung-restricted autoimmunity through the dysfunction of immune mechanisms which maintain peripheral tolerance.


LTx, Lung transplantation;

MHC, Major histocompatibility complex;

HLA, Human leukocyte antigen;

AEC, Airway epithelial cells;

Col-I, Collagen type I;

Col-V, Collagen type V;

KAT, k-alpha 1 tubulin;

PGD, Primary graft dysfunction;

AMR, Antibody-mediated rejection;

MICA, MHC class I-related chain A;

Tregs, Regulatory T cells;

TCR, T cell receptor;

Tconvs, Conventional T cells;

Teffs, Effector T cells;

STAT3, Signal transducer and activator of transcription 3;

BMT, Bone marrow transplantation;

CAR, Chimeric antigen receptor;

Ag, Antigen;

CTL, Cytotoxic T cell;

BOS, Bronchiolitis obliterans syndrome;

EV, Extracellular vesicles;

DCs, Dendritic cells;

CLAD, Chronic lung allograft dysfunction;

SAgs, Self-Antigens







Figure Legends, and Figures


Lung transplantation is the most recognized treatment for advanced stage lung disease. Since the 1990s more than 62000 lung transplants have been completed worldwide (International Society of Heart and Lung Transplantation data). Recent statistics on single-lung transplants show that 78% of patients survive the first year and 51% of patients survive 5 years (NIH) which is significantly lesser compared to other solid organ transplants, including kidney and heart transplants which have 85% and 75% survival after 5 years, respectively.

Post lung transplant patients are subjected to various immune/non-immune dependent factors including recipient age, graft ischemic time, gastro-esophageal reflux disease, metalloproteinase degradation, and microbial infection, which have been associated with the development of inflammatory environment within the transplanted graft (Bharat and Kreisel 2018). The less survival rate among lung transplant patients can be attributed to the development of airflow obstruction known as bronchiolitis obliterans (BO) and Primary graft rejection (PGD) thereby leading to graft rejection (Morrell, Pilewski et al. 2014).

Bronchiolitis obliterans syndrome (BOS) is indicated by inflammation of airway epithelium which leads to fibro- proliferation, and finally to obliterative bronchiolitis. BO typically is associated with chronic lung graft rejection and microbial infections which are opportunistic might affect the quality of life and mortality in long term survivors. PGD represents lung dysfunction that occurs in the first 72 hours of transplantation characterized by hypoxemia and pulmonary infiltrates on radiographs lacking any other justification. PGD remains a significant issue with reported incidence still at about 25%. Higher PGD incidences are mainly associated with chronic lung allograft rejection. Different interventional approaches are being researched upon to recognize the patients who are at high risk for developing BO and PGD to increase the positive outcomes.

The allo and auto-immunity are known to be possibly connected to each other and further to chronic rejection (CR). Administration of antibodies to lung associated self-antigens (SAgs) 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 thymus-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 (Bharat and Mohanakumar 2017). It is expected that further studies will allow the prevention of post-transplant immune complications. Studies considering the humoral immune responses in LTx rejection have disclosed the role of donor specific antibodies (DSA) in acute and CR. This review is to show the importance of non-HLA specific antibodies in the Ltx and briefly summarize the mechanisms of injury.


Allo-immunity acts by producing antibodies through direct or indirect recognition.Indirect 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 since the pathway is based on the higher affinity of allo-antigens by T cells as compared to the other antigens. This pathway is the foremost in responses leading to acute rejection (Afzali, Lombardi et al. 2008). It was demonstrated that dendritic cells (DCs) primarily elicit the direct pathway as diminishing the donor DCs led to immunogenicity failure. It was then normalized subsequent to addition of the DCs. A study conducted by (Lakkis, Arakelov 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 takes place when the processed antigen of donor origin is presented to recipient T cells by APC (Lawrence 1990, Herrera, Golshayan et al. 2004). In certain circumstances, the indirect pathway independent of direct pathway leads to acute graft rejection.

There is some evidence for another pathway called the semi-direct for instance, in a study where cells lacking APC were rejected even in the absence of the indirect recognition (Pimenta-Araujo, Mascarell et al. 2001). Recipient APCs that acquire donor MHC through cell-to-cell contact and activate host T cell responses may contribute to chronic rejection (CR). Further, recipient without MHC class II or indirect recognition mechanism could reject the allogeneic grafts. The semi-direct pathway was debated to be three-cell or four-cell linked initially. The three cell model proposed that CD4+ and CD8+ T cell interactions are activated by same APCs to produce an immune response (Ridge, Di Rosa et al. 1998). CD4+ T cells activated through the indirect mechanism might be involved in either augmentation or normalization of allo-specific CD8+ T cells (Lee, Grusby et al. 1994, Wise, Bemelman et al. 1998).

The contrasting idea of a four-cell/unlinked model believed that the CD8+ cells and CD4+ T cells are stimulated by the 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 alloreactive T cells (Bedford, Garner et al. 1999). 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 (Game, Rogers et al. 2005) or through exosomes, along with activating the direct pathway CD8+ T cells (Morelli, Larregina et al. 2004, Afzali, Lombardi et al. 2008). Allo-antibody can elicit complement deposition and neutrophil infiltration which are features of acute rejection, as well as cellular proliferation and vascular lesion formation, characteristic of CR.


PGD along with OB is the major cause of early mortality in patients after the transplant.  The emerging role of de novo and preexisting autoantibodies in lung transplant is being evaluated. Our group recently reported that lung restricted auto-antibodies, collagen (Col) type V and K-α1 tubulin (KAT) are involved in the mediation of rejection after lung transplant (Bharat, Chiu et al. 2016). Lung SAgs are normally deleted in the thymus. The SAgs which escape thymic deletion are suppressed by SAg specific CD4+CD25+Foxp3+ regulatory T-cells (Tregs) and are present in sequestered form.

Lung SAgs such as Col (v) and KAT 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 (IRI) after the transplant, the matrix metalloproteinase unmasks the col (v) by cleaving it which corresponds with its detection from 4 hours- 30 days post-transplant (Linsenmayer, Gibney et al. 1993, Zheng, Ward et al. 1997, Burlingham, Love et al. 2007, Iwata, Chiyo et al. 2008). It is believed that these self-antigens are transported in the form of blebs to the surface during apoptosis which is a common characteristic of lung injury after transplant (Sorice, Pittoni et al. 2000), which later leads to autoimmunity (Wilkes 2012). It is well recognized that T cells play an important role in distinguishing self and non-self-antigens. Activated CD4+ T cells are known to differentiate into either Th1, Th2 or Th17 phenotypes, characterized by the production of specific cytokines and are mutually regulated.

Regulatory circuit’s such as Tregs are found in many different tissues and are significant in immune tolerance (King 2011) by suppressing inflammation and autoimmune response. Tregs impact the development of autoimmunity in lung transplant recipient and are necessary to initiate the antibodies. Since LTx patients undergo several repeated injury and repair, this might lead to an expansion of SAgs possibly because of sequestered Sags release, epitope spreading and reduction of activation thresholds (Bharat and Mohanakumar 2017). Most Ltx recipients develop de novo antibodies in less than 3 years after the transplant. (Subramanian, Ramachandran et al. 2014, Bharat and Mohanakumar 2017). 

Development of non-HLA antibodies: The two hit hypothesis

The levels of Tregs reduce due to lower respiratory viral infections in lung recipients probably via inducing apoptosis as recipient immunization against the virus protected the Tregs. Clinically, our group established that these viral infections are linked with the Tregs reduction and were concomitant with increase in autoantibody levels. Clinical and experimental studies in human and mice models, respectively indicate the probable role of Tregs in modulating the tolerance against self-Ags present in the lungs.  The Tregs levels are insufficient to initiate the autoimmune response in lungs and autoimmunity cannot develop without the stimulation in their expansion. Therefore, we proposed a “two-hit” mechanism where loss of Tregs combined with the lung injury is required to induce lung-restricted autoimmunity.

We injected anti-MHC class I antibodies intra-tracheally combined with sendai virus infection and found the develop­ment of humoral and cellular autoimmunity against specifically lung-restricted SAgs, namely Col-V and KAT. Also, we noted that lung restricted autoimmunity was induced with injection of hydrochloric acid (to mimic gastro esophageal reflux) and diphtheria toxin only in combination elicited lung restricted autoimmunity and there was no immune response against non-lung antigens. LTx patients are expected to have continuing lung injury from the lung disease for which they are undergoing transplant, therefore our hypothesis stands relevant that they have a pre-existing auto-antibodies.

In instances when due to viral infections these patients undergo Tregs loss, it is probable that they can have lung-restricted autoim­munity. LTx patients who had gastro-esophageal reflux and developed respiratory infections and Tregs level reduction established de novo lung-restricted autoimmunity (Chiu, Fernandez et al. 2016, Akbarpour and Bharat 2017).

Linking auto and alloimmunity

The presence of humoral immunity in allograft rejection is already known. Airway epithelial cells are one of the important targets in lung graft rejection. Anti-Major Histocompatibility Complex class I (MHC I) molecules stimulate airway obliteration by the release of various fibrogenic factors such as, basic fibroblast growth factor (b- FGF), granulocyte-monocyte colony-stimulating factor (GM-CSF) and transforming growth factor-beta (TGF-beta) (Bharat and Mohanakumar 2017). We found that administering anti-MHC I Ab to different mice strain induced epithelial hyperplasia and fibrosis. Moreover, IL-17 levels increased which further induced T-cells against SAgs including KAT and col (V).

We have demonstrated that in lung transplant patients binding of the anti-K-α1 tubulin to the epithelial cells increased expression of the transcription factor, TCF5, mediating inflammatory response genes and expression of signaling proteins such as protein kinase-C (PKC), vascular endothelial growth factor or TGF-β. Also, TCF5 and TGF-β possibly affect the fibro-proliferation cascade which leads to BO subsequent to the lung transplantation. (Goers, Ramachandran et al. 2008). KAT Abs also increase expression of hypoxia-inducible factor (HIF-1α) and inhibition of the HIF-1α normalized the fibrotic growth factor levels.  It is suggested that induction of KAT Ab upregulates HIF-1α mediated fibrogenesis after the LTx.  However, additional studies are needed to identify the mechanisms of autoantibody-induced pathology following LTx.

Autoimmunity prior to transplantation

Several studies have shown the evidence of pre-existing auto-antibodies in solid organ transplant. Bobadilla et al also found that about 58% of patients with idiopathic pulmonary fibrosis and 16% of patients without idiopathic pulmonary fibrosis have anti-col (V) immunity detected by using the trans-vivo mouse footpad delayed-type hypersensitivity model.

When lung transplant patients were assessed for the presence of auto-antibodies, 28% were found to have at a minimum of a single auto-Ab against the SAgs which included col I, col (V) and KAT. DSA can be directed against different classes of HLA and non-HLA antigens which are expressed on epithelial and endothelial cells. However, there is a variation in incidences of de novo DSA following transplant as noted by Hachem et al that 56% patients developed DSA compared to Lobo et al. who detected 29.5% DSA development in 557 days after transplantation.

Mechanisms for non-HLA mediated lung graft rejection

Complement activation

There is ample evidence from animal and human studies pointing to the complement pathway being one of them, possibly intertwined with the other pathways. This is more likely as the multiple functions of the complement products in inflammation, chemotaxis, and interaction with the coagulation cascade are being found. We have reported earlier that auto-Ab against self-antigen col (V) caused injury to epithelial cells post-Ltx in a complement system mediated form. There are there main complement dependent pathways: classical, alternative and lectin (Figure). MAC is an assembly of complement products (C5b-9) responsible for cell lysis with C6 as one of the essential components.

Researchers have used knockout models and complement-deficient animals to study the effects of various components in transplant. The complement activation can be confirmed with vascular C4d deposition to detect antibody-mediated rejection (AMR) in transplantation (LTx). The complement system is recognized in modulating adaptive immune responses, IRI, early graft dysfunction and rejection in organ transplants including both humans and animal studies. In several studies, the lysis complex (C5b-9) decreased along with the lytic activity in complement receptor type 1 inhibitor-treated rats in comparison to control animals. Further, the recipient survival was improved along with a decrease in pulmonary vascular resistance, and neutrophil infiltration (p < .05).

C1 esterase inhibitor inhibition and leukocyte adhesion by complement receptor type 1 inhibitor glycosylated with sialyl Lewis X led to mitigation of some effects of PGD. Since the complement activation starts within the donor allograft, using complement inhibitors in the donor appears to prospective for reducing graft rejection. The studies in humans have shown higher plasma C5a levels post-transplantation in patients with PGD (p =.01) and mortality (Shah, Emtiazjoo et al. 2014). Complement subcomponents or by-products, including C3d and C4d in the allograft, are found to be associated with PGD and early BO. This shows the importance of complement activation and its products in the mediation of lung graft rejection thought human studies are limited. In a recent trial, short-term complement inhibition with TP10 resulted in a significant decrease in the number of days on a ventilator (Keshavjee, Davis et al. 2005).

Recent studies have implicated the impact of non-HLA antibodies with respect to complement activation on lung transplantation outcomes (12.5% for complement fixing DSA vs 62.5% for non-complement-fixing DSAs). In studies using complement knockout animal models to investigate the role of the MAC in orthotropic lung allografts increased injury and macrophages were reported in capillaries when the C6 source was the donor. On the other hand, macrophage increase in pulmonary arteries was observed when C6 were recipient-derived which pointed towards the compartment-specific complement response (Feucht, Felber et al. 1991).

IL-17 mediated regulation of immune response to autoantigens could be enhanced by complement activation. In a study by Suzuki et al., 2013, the down-regulation of complement regulatory protein (CRP, Complement receptor 1-related gene/protein y (Crry) in human and mice OB; and up-regulation of C3a (complement activation marker) was noted. Neutralizing IL-17 could improve CRP expression in mice lung and reduced C3a production while neutralizing C5 revoked OB progression, acute rejection, and reduced levels of C3a, C5a, IL-17 and improved CRP expression. This shows OB progression might be complement dependent proposing that targeting the complement system could be an approach to prevent OB (Suzuki, Lasbury et al. 2013).

C4d deposition is presently the only marker in use for antibody-mediated damage although its use is not universal due to varying results from different investigators. (Aguilar, Carpenter et al. 2018) conducted a single‐center study to correlate C4d with antibody-mediated rejection to find C4d‐positive patients had neutrophilic capillaritis among (Snyder, Wang et al. 2013) C4d+ and C4d- patients. C4d deposition does not appear to be a necessary criterion for the diagnosis. Although the complement split product C4d is now used widely as a pathological marker of AMR, there is much to be learned about the effects of complement activation on rejection processes.

The influence of complement products on neutrophils and macrophages are well-known, and recent reports suggesting its impact on platelet interactions with endothelial cells and leukocytes, B and T cells, add new magnitudes to the effect of innate immunity on adaptive immunity which is relevant to the pathogenesis of acute and chronic organ rejection. (Murata and Baldwin 2009, Ali, Pavlisko et al. 2018).

The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts but is not established in lung transplantation (LTX). In a study, C4d deposition was evaluated in 192 lung transplant biopsies from 32 patients. 16 patients were found to develop HLA-Ab, while the other half of the patients were negative. When C4d staining was compared in 18 other LTx patients without HLA-Ab but in the presence of CMV-pneumonitis/ and or IRI, C4d deposition was noted in 31% patients with HLA-Ab and was absent in the rest of the patients without HLA-Ab ( p < 0.05) which suggested to limit clinical use in protocol biopsies (Ionescu, Girnita et al. 2005).

Th17 cells specific to self-Ags

The innate immune system recognizes pathogens and produces cytokines which further modulate the differentiation of naïve T cells into effector T cells. Recent findings have revealed that T cell differentiates into various subsets including, T helper-1(Th-1) and Th-2, regulatory cells, follicular helper cells, and Th17 cells. Th17 belong to a new effector T cell lineage cells are associated with the pathogenesis of autoimmune disease, immune pathogenesis and play a significant part in host defense.(Shilling and Wilkes 2011) (Weaver, Hatton et al. 2007)  IL-17, or IL-17A, produced mainly by CD4+ T cells, and also by γδ T cells, Natural killer cells, CD8+ T cells, and neutrophils. IL-17 produced from γδ T cells has an important role in ischemia-reperfusion injury and is concomitant to the lung graft rejection after transplant(Wilkes 2012). However, in the study by Snell et al did not find a relation of IL-17 positive cells in rejection (Snell, Levvey et al. 2007).

Despite the inconsistency in the correlation between IL-17 and acute lung transplant rejection, IL-17 might possibly have crucial roles in OB as well as PGD. Increased levels of IL-6, Il-1b, TGF-b which eventually induce IL in a study were increased in BOS. Further, neutralizing IL-17A or augmenting IL-10 was suggested to be used to prevent OB. (Fan, Benson et al. 2011).   Murine lung ischemia-reperfusion injury, that may reproduce clinical PGD, was dependent on IL-17 production derived from natural killer T cells (Sharma, LaPar et al. 2011, Wilkes 2012). Also, IL-17 is fibrotic in lungs which correlates with OB being a fibrotic condition(Wilson, Madala et al. 2010).

T helper 17 (Th17)-dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To explore the basis of these responses, we investigated whether the removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients.

Although the latter responded well to α1 (V) fragments and peptides in an HLA-DR-restricted fashion, Th17 cells from healthy persons responded in an HLA-DR-restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis. (Sullivan, Jankowska-Gan et al. 2017)

Ligands for non-HLA antibodies

It is proposed that the sequestered antigens are released mainly by molecular mimicry and bystander activation, the release of the sequestered self-Ags, lowering of activation thresholds of self-reactive lymphocytes and epi­tope spreading. Proposed that once Abs are bound to one of the SAgs, it leads to opsonization of the membrane by Ag-presenting cells leading to further activation, phenotypic switch leading to an immune response to all the antigens present on the phagocytized membrane leading to spreading of immune responses to other SAgs, and likely to alloantigens in allografts.

Collagen type I, collagen type V and KAT

Autoantibodies against self-antigens have also been linked to rejection after solid organ transplantation. Our group previously reported that the presence of autoantibody against the self-proteins Collagen type I, collagen type V and K-alpha-1 tubulin correlate with a significant increase in the incidence of PGD in patients. KAT Abs ligate to induce HIF-1α -facilitated up-regulation in fibrosis advancement which eventually leads to chronic rejection of lung allograft (Tiriveedhi, Gautam et al. 2013). De novo production of anti-col(V) and K-α1 tubulin antibodies following transplantation is not necessary for generation of lung allograft injury although their presence before the transplant was related to PGD in transplant (Iwata, Chiyo et al. 2008, Bharat, Saini et al. 2010). This possibly shows a need to focus on the autoimmune status of the recipient before the transplant to reduce the graft rejection. Iverson’s group found several other autoantibodies (IgG and IgM isotype) related to lung which are involved in the modulating cellular processes and sometimes to PGD initiation. (Hagedorn, Burton et al. 2011)

Endothelial antigenic targets: Antibodies to GPCRs: Angiotensin-II type 1 receptor (AT1R) and endothelin type A receptor (ETAR)

Non-HLA antibodies specific for anti-AT1R and anti-ETAR (IgG1 and IgG3 subclasses) were found to be linked to renal allograft injury since they induce signaling pathways which are important in vascular injury (Banasik, Boratynska et al. 2014). Antibodies to AT1R or ETAR are often with C4d negative rejection phenotype. Henceforth, graft rejection can be initiated by endothelial injury specific to non-HLA antibodies with complement-mediated injury (Günther, Kill et al. 2014).


Vimentin, found in mesenchymal cells, intermediate filament protein, is integral to support organelles and cell shape maintenance. In a recent study, vimentin expression increased significantly in transplanted lungs when compared to normal the small airway epithelial cells of transplanted lungs and BO airway remodeling (Chong Zhang et al., 2017). Expression of vimentin as a potential predictive biomarker for therapy against lung cancer has also been suggested (Danielsson, Peterson et al. 2018).


MHC class I-related chain A (MICA), a glycoprotein expressed on cellular membrane and its expression is correlated to cellular stress. Abs to MICA after solid organ transplantation has been associated with chronic rejection. It appears that anti-HLA often precedes the development of anti-MICA, and peak titers of anti-MICA are present at the time of clinical diagnosis of chronic lung allograft rejection (Stephens 2001, Sumitran-Holgersson 2008).

Perlecan: Involved in acute rejection

Perlecan (heparan sulfate proteoglycan 2, HSPG2), is a 4391 amino acid long, 460 kDa proteoglycan synthesized by several cells including leucocytes. It is an important component of cells and modulates cell growth, differentiation, death, lipid metabolism, osteophyte formation and a variety of similar functions in complex tissues. It has five domains for glycosaminoglycan attachment, three of which are situated in domain I and comprise of HS, and two in domain V comprise of chondroitin and/or keratan sulfate (CS and KS respectively(Chuang, Lord et al. 2010, Rnjak-Kovacina, Tang et al. 2016).

Domain II of perlecan attached mainly with low-density lipoproteins depicting its importance in lipid retention. There are many biological functions ascribed to perlecan including playing central roles in regulating the assembly of the ECM and the binding and presentation of growth factors to cells. In the lungs, airway Smooth muscle cells from COPD patients presented augmented perlecan production subsequent to SMAD directed TGFβ1 activation. Parenchymal tissue fibroblasts being comparatively more sensitive to TGFβ1 expression caused augmented VEGF and perlecan synthesis(Lord, Tang et al. 2018). In the study conducted by (Malmström, Larsen et al. 2002) showed augmented perlecan secretion in fibrotic cell biopsies samples when compared to normal.

The importance of self-antigens, K-α tubulin and collagen V in lung allograft rejection is already implicated. A study was conducted by  (Reinsmoen, Mirocha 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 which corresponds to the role of Perlecan in acute rejection.


Non-Human Leukocyte Antigen Antibody,Anti-A1 was recently found by (Vinson, Rampolla-Selles et al. 2018) in a patient during single lung transplant. Both Donor and recipient blood group were A positive and no pre-transplant DSA were found. After one week the patient starts showing signs of abnormalities of the grafted lung. Even though High-dose steroids and therapeutic plasma exchanges were instigated for possible acute rejection newly developed anti-A1 red blood cell antibody was identified leading to mortality.

Donor-Derived Exosomes with Lung Self-Antigens

Exosomes, a subclass of extracellular vesicles which express SAgs can be located post solid organ transplantation. Our group studied the role of exosomes post lung transplantation and outlined that lung-associated self-antigens (K-alpha 1 Tubulin and collagen V) were found in exosomes. We suggested that these molecules can possibly be used as non-invasive biomarkers to indicate graft rejection.


Lung transplantation is different from other solid organ transplants as the lungs experience constant stimuli from an open environment, which might indicate the immune system responses. Existing immunosuppression therapies strategies directing the T-cell responses are not promising, and alternative approaches are required.In this review we have discussed SAgs and their importance in LTx. Approaches to distinguish and diminish antibodies against SAgs can be used therapeutically to decrease PGD and graft rejection after LTx. Potential clinical trials are essential to investigate the ability of antibody-directed therapy in patients.


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