We are pleased to present the first collection dedicated to highlighting the research of our Editorial Board, entitled Editors’ Showcase: Transplantation Immunology. This exclusive collection is open to Editorial Board members only, and will feature high-quality contributions from our Associate and Review Editors. Specialty Chief Editor Professor Reza Abdi leads this initiative which will focus on new insights, novel developments, current challenges, latest discoveries, recent advances, and future perspectives in the field of Transplantation Immunology. The work presented here celebrates the broad diversity of research performed across the section and aims to put a spotlight on all areas of interest to our Editors. This collection aims to further support Frontiers’ strong community by recognizing and promoting the work of highly deserving Editors.

Brigham and Women's Hospital, Harvard Medical School

Celebrate the latest insights and developments in Transplantation Immunology with this special collection.

. Recent research has focused on improving diagnosis and monitoring of native kidney diseases and allograft rejection in transplant patients through the use of liquid biopsy techniques. Additionally, Imlifidase, a recombinant cysteine protease, has been conditionally approved in the EU as a desensitizing agent for highly sensitized kidney transplant patients. Single nuclei RNA-sequencing was used to uncover the cellular landscape and transcriptome of normal kidney allografts, providing insight into potential immune cells underlying subclinical inflammation and repair. Furthermore, Leukocyte immunoglobulin-like receptors (LILRs) were mapped at single cell level in the context of kidney transplant rejection, emphasizing non-classical monocytes and CD68+ M cells. <ul> <li>Liquid biopsy techniques have potential to improve diagnosis and monitoring of native kidney diseases and allograft rejection.</li> <li>Imlifidase, a recombinant cysteine protease, has been conditionally approved in the EU as a desensitizing agent.</li> <li>Single nuclei RNA-sequencing has revealed potential immune cells underlying subclinical inflammation and repair.</li> <li>Leukocyte immunoglobulin-like receptors (LILRs) mapped at single cell level in the context of kidney transplant rejection.</li> </ul>

Frontiers in Transplantation

Transplantation Immunology

Editors' Showcase: Transplantation Immunology

The current tools for diagnosing and monitoring native kidney diseases as well as allograft rejection in transplant patients are suboptimal. Creatinine and proteinuria are non-specific and poorly sensitive markers of injury. Tissue biopsies are invasive and carry potential complications. In this article, we overview the different techniques of liquid biopsy and discuss their potential to improve patients’ kidney health. Several diagnostic, predictive, and prognostic biomarkers have been identified with the ability to detect and monitor the activity of native kidney diseases as well as early and chronic allograft rejection, such as donor-derived cell-free DNA, exosomes, messenger RNA/microsomal RNA, proteomics, and so on. While the results are encouraging, additional research is still needed as no biomarker appears to be perfect for a routine application in clinical practice. Despite promising advancements in biomarkers, the most important issue is the lack of standardized pre-analytical criteria. Large validation studies and uniformed standard operating procedures are required to move the findings from bench to bedside. Establishing consortia such as the Liquid Biopsy Consortium for Kidney Diseases can help expedite the research process, allow large studies to establish standardized procedures, and improve the management and outcomes of kidney diseases and of kidney transplant recipients.

The current tools for diagnosing and monitoring native kidney diseases as well as allograft rejection in transplant patients are suboptimal. Creatinine and proteinuria are non-specific and poorly sensitive markers of injury. Tissue biopsies are invasive and carry potential complications. In this article, we overview the different techniques of liquid biopsy and discuss their potential to improve patients&#x2019; kidney health. Several diagnostic, predictive, and prognostic biomarkers have been identified with the ability to detect and monitor the activity of native kidney diseases as well as early and chronic allograft rejection, such as donor-derived cell-free DNA, exosomes, messenger RNA/microsomal RNA, proteomics, and so on. While the results are encouraging, additional research is still needed as no biomarker appears to be perfect for a routine application in clinical practice. Despite promising advancements in biomarkers, the most important issue is the lack of standardized pre-analytical criteria. Large validation studies and uniformed standard operating procedures are required to move the findings from bench to bedside. Establishing consortia such as the Liquid Biopsy Consortium for Kidney Diseases can help expedite the research process, allow large studies to establish standardized procedures, and improve the management and outcomes of kidney diseases and of kidney transplant recipients.

Liquid biopsy for non-invasive monitoring of patients with kidney transplants

The IgG-degrading enzyme derived from Streptococcus pyogenes is a recombinant cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four human subclasses of IgG with strict specificity. The proteolytic activity on IgG molecules prevents the occurrence of IgG-mediated antibody-dependent, cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for antibody rejection. The results from phase II studies demonstrated that desensitization with imlifidase represents a therapeutic strategy that can operationalize desensitization, allowing life-saving transplants from deceased donors (DD) and living donors (LD) to proceed in highly sensitized kidney transplant candidates with low risk of hyperacute rejection. Its action onset is rapid, allowing kidney transplantation from a deceased donor. Disadvantages of imlifidase include a quick reappearance of DSAs, which poses a risk of antibody-mediated rejection, the quick development of anti-Ides antibodies, which rules out repeated use of imlifidase and its IgG-degrading potential, limiting the use of therapeutic antibodies. Imlifdase received conditional approval on 26 August 2020 in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

The IgG-degrading enzyme derived from Streptococcus pyogenes is a recombinant cysteine protease of S. pyogenes produced in Escherichia coli that cleaves all four human subclasses of IgG with strict specificity. The proteolytic activity on IgG molecules prevents the occurrence of IgG-mediated antibody-dependent, cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for antibody rejection. The results from phase II studies demonstrated that desensitization with imlifidase represents a therapeutic strategy that can operationalize desensitization, allowing life-saving transplants from deceased donors (DD) and living donors (LD) to proceed in highly sensitized kidney transplant candidates with low risk of hyperacute rejection. Its action onset is rapid, allowing kidney transplantation from a deceased donor. Disadvantages of imlifidase include a quick reappearance of DSAs, which poses a risk of antibody-mediated rejection, the quick development of anti-Ides antibodies, which rules out repeated use of imlifidase and its IgG-degrading potential, limiting the use of therapeutic antibodies. Imlifdase received conditional approval on 26 August 2020 in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

New approach to desensitization in solid organ transplantation-imlifidase

Despite recent advances made in short-term outcomes; minimal improvements have been observed in long-term kidney transplantation outcomes. Due to an imbalance between organ transplant availability and patient waiting list, expanding kidney allograft longevity is a critical need in the field. Prior studies have either focused on early ischemic and immunological conditions affecting kidney allografts (e.g., delayed graft function, acute rejection) or late stage chronic injury when interventions are no longer feasible. However, studies characterizing kidney allografts with normal function by its cellular distribution, cell-cell interactions, and associated molecular pathways are lacking. Herein, we used single nuclei RNA-sequencing to uncover the cellular landscape and transcriptome of the normal kidney allograft. We profiled 40,950 nuclei from seven human kidney biopsies (normal native, N = 3; normal allograft, N = 4); normal allograft protocol biopsies were collected ≥15-months post-transplant. A total of 17 distinct cell clusters were identified with proximal tubules (25.70 and 21.01%), distal tubules (15.22 and 18.20%), and endothelial cells (EC) (4.26 and 9.94%) constituting the major cell populations of normal native and normal allograft kidneys, respectively. A large proportion of cycling cells from normal native kidneys were in G1-phase (43.96%) whereas cells from normal allograft were predominantly in S-phase (32.69%). This result suggests that transcriptional differences between normal native and normal allograft biopsies are dependent on the new host environment, immunosuppression, and injury-affliction. In the normal allograft, EC-specific genes upregulated metabolism, the immune response, and cellular growth, emphasizing their role in maintaining homeostasis during the ongoing alloreactive stress response. Immune cells, including B (2.81%), macrophages (24.96%), monocytes (15.29%), natural killer (NK) (12.83%), neutrophils (8.44%), and T cells (14.41%, were increased in normal allografts despite lack of histological or clinical evidence of acute rejection. Phenotypic characterization of immune cell markers supported lymphocyte activation and proinflammatory cytokines signaling pathways (i.e., IL-15, IL-32). The activation of B, NK, and T cells reveals potential immune cells underlying subclinical inflammation and repair. These single nuclei analyses provide novel insights into kidney and immune cell associated signaling pathways that portray kidney grafts with normal allograft function beyond 2-years post-transplant, revealing a novel perspective in understanding long-term allograft graft survival.

Despite recent advances made in short-term outcomes; minimal improvements have been observed in long-term kidney transplantation outcomes. Due to an imbalance between organ transplant availability and patient waiting list, expanding kidney allograft longevity is a critical need in the field. Prior studies have either focused on early ischemic and immunological conditions affecting kidney allografts (e.g., delayed graft function, acute rejection) or late stage chronic injury when interventions are no longer feasible. However, studies characterizing kidney allografts with normal function by its cellular distribution, cell-cell interactions, and associated molecular pathways are lacking. Herein, we used single nuclei RNA-sequencing to uncover the cellular landscape and transcriptome of the normal kidney allograft. We profiled 40,950 nuclei from seven human kidney biopsies (normal native, N = 3; normal allograft, N = 4); normal allograft protocol biopsies were collected ≥15-months post-transplant. A total of 17 distinct cell clusters were identified with proximal tubules (25.70 and 21.01%), distal tubules (15.22 and 18.20%), and endothelial cells (EC) (4.26 and 9.94%) constituting the major cell populations of normal native and normal allograft kidneys, respectively. A large proportion of cycling cells from normal native kidneys were in G1-phase (43.96%) whereas cells from normal allograft were predominantly in S-phase (32.69%). This result suggests that transcriptional differences between normal native and normal allograft biopsies are dependent on the new host environment, immunosuppression, and injury-affliction. In the normal allograft, EC-specific genes upregulated metabolism, the immune response, and cellular growth, emphasizing their role in maintaining homeostasis during the ongoing alloreactive stress response. Immune cells, including B (2.81%), macrophages (24.96%), monocytes (15.29%), natural killer (NK) (12.83%), neutrophils (8.44%), and T cells (14.41%, were increased in normal allografts despite lack of histological or clinical evidence of acute rejection. Phenotypic characterization of immune cell markers supported lymphocyte activation and proinflammatory cytokines signaling pathways (i.e., IL-15, IL-32). The activation of B, NK, and T cells reveals potential immune cells underlying subclinical inflammation and repair. These single nuclei analyses provide novel insights into kidney and immune cell associated signaling pathways that portray kidney grafts with normal allograft function beyond 2-years post-transplant, revealing a novel perspective in understanding long-term allograft graft survival.

The cellular landscape of the normal kidney allograft: Main players balancing the alloimmune response

Leukocyte immunoglobulin-like receptors (LILRs) are a family of inhibitory or stimulatory receptors expressed by immune cell types belonging to both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I and thus play important roles in a range of clinical situations including pregnancy. Moreover, paired immunoglobulin-like receptors (PIRs), the murine orthologs of LILRs, are implicated in experimental transplant allorecognition by monocytes and contribute to the induction of donor-specific monocyte-memory. After non-self recognition, activating PIRs are transiently overexpressed at the surface of monocytes and participate in donor-specific monocyte recruitment, leading to graft rejection in vivo. In the present study, we mapped LILR expression and also their respective reported ligands at single cell level in the renal allograft and circulating cells in the context of kidney transplant rejection. Recipient-derived monocytes were shown to infiltrate the donor tissue and to differentiate into macrophages. We thus also investigate LILR expression during in vitro monocyte-to-macrophage differentiation in order to characterize the myeloid population that directly contribute to allorecognition. Altogether our results emphasize non-classical monocytes and CD68+ M1 macrophages as key players in LILRs-ligand interaction in kidney transplantation.

Leukocyte immunoglobulin-like receptors (LILRs) are a family of inhibitory or stimulatory receptors expressed by immune cell types belonging to both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I and thus play important roles in a range of clinical situations including pregnancy. Moreover, paired immunoglobulin-like receptors (PIRs), the murine orthologs of LILRs, are implicated in experimental transplant allorecognition by monocytes and contribute to the induction of donor-specific monocyte-memory. After non-self recognition, activating PIRs are transiently overexpressed at the surface of monocytes and participate in donor-specific monocyte recruitment, leading to graft rejection in vivo. In the present study, we mapped LILR expression and also their respective reported ligands at single cell level in the renal allograft and circulating cells in the context of kidney transplant rejection. Recipient-derived monocytes were shown to infiltrate the donor tissue and to differentiate into macrophages. We thus also investigate LILR expression during in vitro monocyte-to-macrophage differentiation in order to characterize the myeloid population that directly contribute to allorecognition. Altogether our results emphasize non-classical monocytes and CD68+ M1 macrophages as key players in LILRs-ligand interaction in kidney transplantation.