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Ann Liver Transplant 2022; 2(1): 1-7

Published online May 31, 2022 https://doi.org/10.52604/alt.22.0003

Copyright © The Korean Liver Transplantation Society.

Future-directed studies on immunosuppressive treatments and xenografts for organ transplantation

Jeong-Ik Park1 , Bo Hyun Jung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea 
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: March 11, 2022; Revised: March 17, 2022; Accepted: March 19, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Marked development has led to significant improvements in the outcomes of organ transplantation. With the development of surgical techniques and immunosuppression, organ transplantation has become the ultimate treatment for patients with end-stage organ failure. Although the short-term transplant results have been improved, long-term outcomes of organ transplantation seem to have reached its limit. Posttransplant immunosuppression is directed toward optimization of the immunosuppressive regimens with conventional immunosuppressive agents for better control of antibodies while avoiding calcineurin inhibitor toxicity and by biological therapeutics including co-stimulation blockade agents that provide effective control of antibodies along with a reduction in the use or avoidance of available immunosuppressive agents. Tolerance induction through transplantation of donor hematopoietic stem cells or infusion of regulatory cells using various sources of immune cells is also a promising strategy because it can lead to avoidance of immunosuppressant-associated complications. Recent results of new immunosuppressants obtained from non-human study models provide valuable information on the optimization of immunosuppressive regimens. The recent initial success of human xenotransplantation using pig kidneys and hearts will give a new insight toward xenotransplantation. All new immunosuppressants and regimens should be validated under the considerations for risk-benefit balance in various clinical conditions. Future immunosuppressive therapy strategies are needed to effectively control antibodies and antibody-mediated rejection while avoiding calcineurin inhibitor-associated complications.

Keywords: Organ transplantation, Immunosuppressive agents, Co-stimulatory pathway, Immune checkpoint, Xenotransplantation

The first kidney transplant in 1954, a pancreas transplant in 1966, and a liver transplant in 1967 were successfully performed. With the development of innovative surgical techniques and effective immunosuppressive regimens, organ transplantation has become the ultimate treatment for patients with end-stage organ failure.

Although the short-term transplant results have improved, the long-term outcomes of organ transplantation seem to have reached its limit [1]. Among the factors limiting the improvement of long-term organ transplant performance, nephrotoxicity of calcineurin inhibitors (CNI) is a leading cause of limitation [2,3]; CNI-induced nephrotoxicity is a cause of renal failure in heart, liver transplant, and kidney transplant patients. The other major causes of patient mortality after organ transplantation are cardiovascular diseases, infections, and malignant diseases [4,5] which are attributed to the occurrence and exacerbation of metabolic diseases such as hypertension and increased risk of malignant diseases. Antibody mediation through de novo donor-specific antibody (dnDSA) and antibody-mediated rejection are known to be the main causes of graft dysfunction [6]. The occurrence of dnDSA precedes the appearance of graft dysfunction clinically, and microscopic changes precede the appearance of dnDSA [7]. Therefore, effective immunosuppressive regimens to prevent rejection and minimize complications of immunosuppressive drugs are the key toward long-term improvement in organ transplantation [8].

There have been efforts to minimize the well-known CNI side-effects. In CNI immunosuppressive therapy, the balance between CNI and mycophenolate mofetil or mammalian target of rapamycin (mTOR) inhibitor in their combination therapy to minimize the side effects of CNI is a widely accepted concept [9,10]. However, long-term follow-up results have shown that lowering the CNI blood level has a risk of increasing the occurrence of dnDSA.

With the accumulation of experience in organ transplantation, re-transplantation is becoming more frequent. In addition to the past immunological contraindications or high-risk groups, the appearance of dnDSA in the long-term course is more frequent than in the short-term rejection as shown by most immunosuppressant clinical trials even in addition to the immunologically low-risk group [11].

Clinical studies on the long-term effects of dosage reduction and the occurrence of dnDSA in induction and maintenance immunosuppressants are in progress. Among the induction immunosuppressants, it was reported that the incidence of dnDSA was low in the patient group administered with anti-thymocyte globulin, an overall T-cell depleting agent [12], but the comparative analysis is needed with various patient groups.

CNIs immunosuppressive agents require monitoring of blood drug concentrations due to various drug-associated side-effects and complications. However, intra-patient variability has been suggested as one of the factors influencing organ graft dysfunction, and clinical data on whether intra-patient variability of immunosuppressive drugs can affect the long-term graft survival rates are under investigation [13,14].

Improving long-term posttransplant performance in patients with various immunological risk factors requires a combination of immunosuppressant or immunosuppressive therapy; a combination of the currently available immunosuppressive therapy that can effectively suppress long-term dnDSA generation through sensitive antibody monitoring is needed. In addition, suppression of long-term dnDSA generation can be achieved by optimal immunosuppressive agent blood concentration, through patient compliance, during the immunosuppressive therapy conversion process according to the transplantation period. Therefore, the establishment of an optimized monitoring protocol that includes the existing antibody monitoring even under the conventional immunosuppressive agents is necessary for improving long-term prognosis.

Inhibitors of Co-stimulatory Pathway

The co-stimulatory pathway is the main target of immunosuppressants that is expected to reduce the CNI complications. T cell activation by a foreign antigen happens through co-stimulation and cytokine stimulation after signal transduction by T-cell receptors. Among these signals, stimulation by co-stimulation is the most important for T cell activation. When this signal is suppressed, T cells fall into a non-responsive state to foreign antigens; in transplant immunity, it is a key target for regulating the immune response after organ transplantation [15,16]. The co-stimulatory pathway is also called immune checkpoints, and is currently a major target in the field of immunotherapy. Immunotherapy’s mechanism of action is through enhancing the immunity of T cells, but in transplant immunity, it works by suppressing the immunity of the T cells.

Anti-CD154 antibody

The anti-CD154 antibody is a potential immunosuppressant through co-stimulatory pathway inhibition. In preclinical primate experiments, the T-cell regulatory function of the anti-CD154 antibody has been well demonstrated in various transplantation models. While clinical trials were stopped due to serious side-effects [17], it has been reported that the use of anti-CD154 antibody is more effective than CTLA-4 immunoglobulin or anti-CD40 antibody in preclinical primate allograft and xenograft studies of various transplant models [18,19].

Anti-CD40 antibody

Iscalimab (CFZ533), an anti-CD40 antibody targeting the CD40/CD40L (CD154) pathway, is under clinical trial for potential use as a CNI replacement immunosuppressant in kidney transplant patients [20]. Another anti-CD40 antibody, bleselumab (ASKP1240), is under clinical trials for de novo in kidney transplantation [21]. Antibody production and antibody-mediated immune response are major immunological factors for graft failure in organ transplantation. It is well known that co-stimulatory inhibitors have an effective inhibitory effect on the humoral immune response [22]. Consequently, there is ongoing intensive research and development of inhibitors as immunosuppressive agents based on allograft and xenograft models. In addition, there have been studies on the role of these co-stimulatory inhibitors in inhibiting antibody production in combination with immunosuppressive agents such as mTOR inhibitors.

CTLA4-immunoglobulin

Belatacept, a TLA4-immunoglobulin, is a co-stimulatory pathway inhibitor that has been approved by the US Food and Drug Administration (FDA) [23]. Experimentally, belatacept was its efficacy in monkey allogeneic kidney and islet transplantation, and was demonstrated as an effective co-stimulatory factor inhibitor and a potential CNI substitute [24,25]. In a preclinical primate sensitization model, it was reported to prevent the humoral rebound of antibody production in the germinal center of lymph nodes after desensitization in a preclinical primate sensitization model [26,27]. Belatacept is known to play a role in suppressing T cells as well as B cells and antibody production, thus it is expected to subsequently suppress antibody production and replace CNI.

Other Biological Treatment Agents for Antibody-Mediated Rejection

Although not as a maintenance immunosuppressant, various immunosuppressants have been used or tried in desensitization therapy after kidney transplantation and the treatment of antibody-mediated rejection. Rituximab is an antibody against CD20, a pan B-cell marker, and has been used as a major therapeutic agent for lymphoma. Although it is not an antibody specific to plasma cells that produce an antibody, it has been used in the organ transplantation field in pretreatment or desensitization therapy as it ultimately modulates the antibody by reducing the overall antibody-producing B cells. Thus, it has been used to overcome the ABO blood group barrier as ABO-incompatible liver and kidney transplantation [28,29]. In addition, bortezomib, a proteosome inhibitor, and a plasma cell-targeted antibody that produces antibodies, has been in use although limited, but clinical results have not met the initial expectations. However, the next-generation anti-CD20 antibody, obinutuzumab [30], and the next-generation proteosome inhibitor, carfilzomib, are being studied [31]. In addition, various biological agents targeting inhibition of various antibody formation, such as complement pathway-targeted C5 inhibitor (eculizumab) and anti-IL-6 receptor antibody (tocilizumab) are being researched [32].

Chimerism through Hematopoietic Stem Cell Transplantation

One of the ideal immunosuppressive strategies for long-term survival that are free from complications and side-effects of immunosuppressants is the induction of immune tolerance that sufficiently maintains stable graft function without immunosuppressive agents. Many researchers have targeted maintaining stable graft function without immunosuppressants. In the history of transplant immunity research and clinical organ transplantation, the phenomenon of mixed chimerism, in which the immune systems of donors and recipients coexist, has been suggested through preclinical processes as a method of inducing immune tolerance. As the first clinical results, Kawai et al. [33] succeeded in discontinuing immunosuppressive drugs after kidney transplantation in four out of five patients who received both bone marrow and kidney transplantation simultaneously. In this study, transient mixed chimerism was induced in transplant patients, and showed long-term immune tolerance induction in recipients after transplantation. Successful induction of immune tolerance through combined kidney and bone marrow transplantation after pretreatment was also reported in Korea [34].

On the other hand, Leventhal et al. [35] performed facilitating cell that induces the generation of antigen-specific regulatory T-cells (Treg) isolated from the donor’s peripheral hematopoietic stem cells at the same time as kidney transplantation. It succeeded in inducing long-term immune tolerance through continuous and robust chimerism. However, the induction of immune tolerance is under investigation [36,37].

Cell Therapy with Treg Cells

One of the main targets for immune tolerance is treatment using Treg cells. Todo et al. [38] successfully induced immune tolerance in 7 out of 10 patients in a living donor liver transplantation pilot study through administration of ex vivo-generated regulatory T-cell-enriched cells. Meanwhile, in the global multicenter study (the ONE study consortium) targeting clinical kidney transplant patients, immunity using various cells including Treg cells such as polyclonal regulatory T-cell, donor alloantigen reactive regulatory T-cell, regulatory donor-derived macrophage, and dendritic cell, various clinical studies on safety and applicability for induction of tolerance are currently under investigation [39]. As for other cell therapies, attempts using mesodermal stem cells, which are known to have immunomodulatory functions, have been also carried out [40].

Preclinical Primate Xenotransplantation Studies

Xenotransplantation is a fundamental solution to the limited supply of organs [41]. Xenotransplantation adopts numerous immunosuppressive strategies mentioned above and it is currently in the preclinical trials stage. CRSPR Cas9 technology has been applied in the development of transgenic pigs, enabling multigene knock-out and knock-in and producing and verifying transgenic pigs.

More than a dozen gene-edited pigs have been made in recent years. In particular, the preclinical primate test results have also been significantly improved, and α1,3-galactosyl transferase (GalT) knock-out in xenogeneic kidney transplantation, using pigs expressing human CD55, reported a graft survival of 499 days in a xenogeneic kidney transplantation model [42]. Meanwhile, in the primate xenograft test field, GalT knock-out, human membrane cofactor protein (CD46), and human thrombomodulin-expressing human thrombomodulin were used for stereotactic xenograft transplantation. A graft survival rate of 195 days has been reported in a primate study [43]. The immunosuppressive agent used in this preclinical primate xenograft model is a combination of anti-CD20, anti-CD4, anti-CD8, anti-thymocyte globulin, anti-CD154, anti-CD40, CTLA4-Ig, and the like. One of the obstacles in the clinical entry stage of xenografts is effective immunosuppressive therapy in xenografts that can be applied clinically. Currently, immunosuppressive agents that are more than clinically applicable immunosuppressants in allografts are required in xenografts. Among these immunosuppressants, clinical applications such as anti-CD40 are already in progress, and anti-CD154 and others are under preclinical primate trials before clinical trials. It is thought that preclinical experimental research on xenografts is playing a forefront role in the development of immunosuppressive agents for allografts.

Initial Human Xenotransplantation

World-first human xenotransplantation with a pig kidney in September 2021

It was reported that a pig kidney was attached to a human patient and the organ function was watched for 54 hours. This was the first time that a pig kidney was transplanted to a human body and was not immediately rejected. The recipient was a brain-dead donor, but her organs were not suitable for donation. A kidney from a genetically engineered pig was attached outside of the human body to assess its function in real-time. The pig’s thymus gland was also transplanted with the kidney to improve its chances of acceptance. Within minutes, the kidney started producing large amounts of urine and showed other signs of normal functioning. The transplant team closely monitored the kidney for 54 hours and saw no signs of rejection [44,45].

World-first human xenotransplantation with a pig heart in January 2022

A 57-year-old male had been on cardiac support for two months and could not receive a mechanical heart pump because of an irregular heartbeat. Neither could he receive a human transplant. Given that he otherwise faced certain death, the researchers got permission from the FDA to transplant a pig heart. To prepare the pig heart for the transplant, the researchers knocked out three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aimed to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized. Ten of those genes in the donor pig had been altered through a time-consuming gene-editing process. The new pig heart was functioning and already doing most of the work; the patient was closely monitored for signs of the new organ rejection, and there was no incident in the first 48 hours, which were critical, passed without incident [46,47]. Two months later, this patient passes away due to pig heart failure of unknown cause [48].

With the development of CNIs, the outcomes of organ transplantation have improved, especially in immunologically low-risk patients. All new immunosuppressants and regimens should be validated under the considerations for risk-benefit balance in various clinical conditions. Immunosuppressive therapy strategies are needed in the future to effectively control antibodies and antibody-mediated rejection while avoiding CNI-associated complications.

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Article

Review Article

Ann Liver Transplant 2022; 2(1): 1-7

Published online May 31, 2022 https://doi.org/10.52604/alt.22.0003

Copyright © The Korean Liver Transplantation Society.

Future-directed studies on immunosuppressive treatments and xenografts for organ transplantation

Jeong-Ik Park1 , Bo Hyun Jung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea 
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: March 11, 2022; Revised: March 17, 2022; Accepted: March 19, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Marked development has led to significant improvements in the outcomes of organ transplantation. With the development of surgical techniques and immunosuppression, organ transplantation has become the ultimate treatment for patients with end-stage organ failure. Although the short-term transplant results have been improved, long-term outcomes of organ transplantation seem to have reached its limit. Posttransplant immunosuppression is directed toward optimization of the immunosuppressive regimens with conventional immunosuppressive agents for better control of antibodies while avoiding calcineurin inhibitor toxicity and by biological therapeutics including co-stimulation blockade agents that provide effective control of antibodies along with a reduction in the use or avoidance of available immunosuppressive agents. Tolerance induction through transplantation of donor hematopoietic stem cells or infusion of regulatory cells using various sources of immune cells is also a promising strategy because it can lead to avoidance of immunosuppressant-associated complications. Recent results of new immunosuppressants obtained from non-human study models provide valuable information on the optimization of immunosuppressive regimens. The recent initial success of human xenotransplantation using pig kidneys and hearts will give a new insight toward xenotransplantation. All new immunosuppressants and regimens should be validated under the considerations for risk-benefit balance in various clinical conditions. Future immunosuppressive therapy strategies are needed to effectively control antibodies and antibody-mediated rejection while avoiding calcineurin inhibitor-associated complications.

Keywords: Organ transplantation, Immunosuppressive agents, Co-stimulatory pathway, Immune checkpoint, Xenotransplantation

INTRODUCTION

The first kidney transplant in 1954, a pancreas transplant in 1966, and a liver transplant in 1967 were successfully performed. With the development of innovative surgical techniques and effective immunosuppressive regimens, organ transplantation has become the ultimate treatment for patients with end-stage organ failure.

Although the short-term transplant results have improved, the long-term outcomes of organ transplantation seem to have reached its limit [1]. Among the factors limiting the improvement of long-term organ transplant performance, nephrotoxicity of calcineurin inhibitors (CNI) is a leading cause of limitation [2,3]; CNI-induced nephrotoxicity is a cause of renal failure in heart, liver transplant, and kidney transplant patients. The other major causes of patient mortality after organ transplantation are cardiovascular diseases, infections, and malignant diseases [4,5] which are attributed to the occurrence and exacerbation of metabolic diseases such as hypertension and increased risk of malignant diseases. Antibody mediation through de novo donor-specific antibody (dnDSA) and antibody-mediated rejection are known to be the main causes of graft dysfunction [6]. The occurrence of dnDSA precedes the appearance of graft dysfunction clinically, and microscopic changes precede the appearance of dnDSA [7]. Therefore, effective immunosuppressive regimens to prevent rejection and minimize complications of immunosuppressive drugs are the key toward long-term improvement in organ transplantation [8].

RECENT EFFORTS FOR MAXIMAL UTILIZATION OF CONVENTIONAL IMMUNOSUPPRESSIVE AGENTS

There have been efforts to minimize the well-known CNI side-effects. In CNI immunosuppressive therapy, the balance between CNI and mycophenolate mofetil or mammalian target of rapamycin (mTOR) inhibitor in their combination therapy to minimize the side effects of CNI is a widely accepted concept [9,10]. However, long-term follow-up results have shown that lowering the CNI blood level has a risk of increasing the occurrence of dnDSA.

With the accumulation of experience in organ transplantation, re-transplantation is becoming more frequent. In addition to the past immunological contraindications or high-risk groups, the appearance of dnDSA in the long-term course is more frequent than in the short-term rejection as shown by most immunosuppressant clinical trials even in addition to the immunologically low-risk group [11].

Clinical studies on the long-term effects of dosage reduction and the occurrence of dnDSA in induction and maintenance immunosuppressants are in progress. Among the induction immunosuppressants, it was reported that the incidence of dnDSA was low in the patient group administered with anti-thymocyte globulin, an overall T-cell depleting agent [12], but the comparative analysis is needed with various patient groups.

CNIs immunosuppressive agents require monitoring of blood drug concentrations due to various drug-associated side-effects and complications. However, intra-patient variability has been suggested as one of the factors influencing organ graft dysfunction, and clinical data on whether intra-patient variability of immunosuppressive drugs can affect the long-term graft survival rates are under investigation [13,14].

Improving long-term posttransplant performance in patients with various immunological risk factors requires a combination of immunosuppressant or immunosuppressive therapy; a combination of the currently available immunosuppressive therapy that can effectively suppress long-term dnDSA generation through sensitive antibody monitoring is needed. In addition, suppression of long-term dnDSA generation can be achieved by optimal immunosuppressive agent blood concentration, through patient compliance, during the immunosuppressive therapy conversion process according to the transplantation period. Therefore, the establishment of an optimized monitoring protocol that includes the existing antibody monitoring even under the conventional immunosuppressive agents is necessary for improving long-term prognosis.

DEVELOPMENT OF NEW IMMUNOSUPPRESSIVE AGENTS

Inhibitors of Co-stimulatory Pathway

The co-stimulatory pathway is the main target of immunosuppressants that is expected to reduce the CNI complications. T cell activation by a foreign antigen happens through co-stimulation and cytokine stimulation after signal transduction by T-cell receptors. Among these signals, stimulation by co-stimulation is the most important for T cell activation. When this signal is suppressed, T cells fall into a non-responsive state to foreign antigens; in transplant immunity, it is a key target for regulating the immune response after organ transplantation [15,16]. The co-stimulatory pathway is also called immune checkpoints, and is currently a major target in the field of immunotherapy. Immunotherapy’s mechanism of action is through enhancing the immunity of T cells, but in transplant immunity, it works by suppressing the immunity of the T cells.

Anti-CD154 antibody

The anti-CD154 antibody is a potential immunosuppressant through co-stimulatory pathway inhibition. In preclinical primate experiments, the T-cell regulatory function of the anti-CD154 antibody has been well demonstrated in various transplantation models. While clinical trials were stopped due to serious side-effects [17], it has been reported that the use of anti-CD154 antibody is more effective than CTLA-4 immunoglobulin or anti-CD40 antibody in preclinical primate allograft and xenograft studies of various transplant models [18,19].

Anti-CD40 antibody

Iscalimab (CFZ533), an anti-CD40 antibody targeting the CD40/CD40L (CD154) pathway, is under clinical trial for potential use as a CNI replacement immunosuppressant in kidney transplant patients [20]. Another anti-CD40 antibody, bleselumab (ASKP1240), is under clinical trials for de novo in kidney transplantation [21]. Antibody production and antibody-mediated immune response are major immunological factors for graft failure in organ transplantation. It is well known that co-stimulatory inhibitors have an effective inhibitory effect on the humoral immune response [22]. Consequently, there is ongoing intensive research and development of inhibitors as immunosuppressive agents based on allograft and xenograft models. In addition, there have been studies on the role of these co-stimulatory inhibitors in inhibiting antibody production in combination with immunosuppressive agents such as mTOR inhibitors.

CTLA4-immunoglobulin

Belatacept, a TLA4-immunoglobulin, is a co-stimulatory pathway inhibitor that has been approved by the US Food and Drug Administration (FDA) [23]. Experimentally, belatacept was its efficacy in monkey allogeneic kidney and islet transplantation, and was demonstrated as an effective co-stimulatory factor inhibitor and a potential CNI substitute [24,25]. In a preclinical primate sensitization model, it was reported to prevent the humoral rebound of antibody production in the germinal center of lymph nodes after desensitization in a preclinical primate sensitization model [26,27]. Belatacept is known to play a role in suppressing T cells as well as B cells and antibody production, thus it is expected to subsequently suppress antibody production and replace CNI.

Other Biological Treatment Agents for Antibody-Mediated Rejection

Although not as a maintenance immunosuppressant, various immunosuppressants have been used or tried in desensitization therapy after kidney transplantation and the treatment of antibody-mediated rejection. Rituximab is an antibody against CD20, a pan B-cell marker, and has been used as a major therapeutic agent for lymphoma. Although it is not an antibody specific to plasma cells that produce an antibody, it has been used in the organ transplantation field in pretreatment or desensitization therapy as it ultimately modulates the antibody by reducing the overall antibody-producing B cells. Thus, it has been used to overcome the ABO blood group barrier as ABO-incompatible liver and kidney transplantation [28,29]. In addition, bortezomib, a proteosome inhibitor, and a plasma cell-targeted antibody that produces antibodies, has been in use although limited, but clinical results have not met the initial expectations. However, the next-generation anti-CD20 antibody, obinutuzumab [30], and the next-generation proteosome inhibitor, carfilzomib, are being studied [31]. In addition, various biological agents targeting inhibition of various antibody formation, such as complement pathway-targeted C5 inhibitor (eculizumab) and anti-IL-6 receptor antibody (tocilizumab) are being researched [32].

INDUCTION OF IMMUNE TOLERANCE

Chimerism through Hematopoietic Stem Cell Transplantation

One of the ideal immunosuppressive strategies for long-term survival that are free from complications and side-effects of immunosuppressants is the induction of immune tolerance that sufficiently maintains stable graft function without immunosuppressive agents. Many researchers have targeted maintaining stable graft function without immunosuppressants. In the history of transplant immunity research and clinical organ transplantation, the phenomenon of mixed chimerism, in which the immune systems of donors and recipients coexist, has been suggested through preclinical processes as a method of inducing immune tolerance. As the first clinical results, Kawai et al. [33] succeeded in discontinuing immunosuppressive drugs after kidney transplantation in four out of five patients who received both bone marrow and kidney transplantation simultaneously. In this study, transient mixed chimerism was induced in transplant patients, and showed long-term immune tolerance induction in recipients after transplantation. Successful induction of immune tolerance through combined kidney and bone marrow transplantation after pretreatment was also reported in Korea [34].

On the other hand, Leventhal et al. [35] performed facilitating cell that induces the generation of antigen-specific regulatory T-cells (Treg) isolated from the donor’s peripheral hematopoietic stem cells at the same time as kidney transplantation. It succeeded in inducing long-term immune tolerance through continuous and robust chimerism. However, the induction of immune tolerance is under investigation [36,37].

Cell Therapy with Treg Cells

One of the main targets for immune tolerance is treatment using Treg cells. Todo et al. [38] successfully induced immune tolerance in 7 out of 10 patients in a living donor liver transplantation pilot study through administration of ex vivo-generated regulatory T-cell-enriched cells. Meanwhile, in the global multicenter study (the ONE study consortium) targeting clinical kidney transplant patients, immunity using various cells including Treg cells such as polyclonal regulatory T-cell, donor alloantigen reactive regulatory T-cell, regulatory donor-derived macrophage, and dendritic cell, various clinical studies on safety and applicability for induction of tolerance are currently under investigation [39]. As for other cell therapies, attempts using mesodermal stem cells, which are known to have immunomodulatory functions, have been also carried out [40].

XENOTRANSPLANTATION

Preclinical Primate Xenotransplantation Studies

Xenotransplantation is a fundamental solution to the limited supply of organs [41]. Xenotransplantation adopts numerous immunosuppressive strategies mentioned above and it is currently in the preclinical trials stage. CRSPR Cas9 technology has been applied in the development of transgenic pigs, enabling multigene knock-out and knock-in and producing and verifying transgenic pigs.

More than a dozen gene-edited pigs have been made in recent years. In particular, the preclinical primate test results have also been significantly improved, and α1,3-galactosyl transferase (GalT) knock-out in xenogeneic kidney transplantation, using pigs expressing human CD55, reported a graft survival of 499 days in a xenogeneic kidney transplantation model [42]. Meanwhile, in the primate xenograft test field, GalT knock-out, human membrane cofactor protein (CD46), and human thrombomodulin-expressing human thrombomodulin were used for stereotactic xenograft transplantation. A graft survival rate of 195 days has been reported in a primate study [43]. The immunosuppressive agent used in this preclinical primate xenograft model is a combination of anti-CD20, anti-CD4, anti-CD8, anti-thymocyte globulin, anti-CD154, anti-CD40, CTLA4-Ig, and the like. One of the obstacles in the clinical entry stage of xenografts is effective immunosuppressive therapy in xenografts that can be applied clinically. Currently, immunosuppressive agents that are more than clinically applicable immunosuppressants in allografts are required in xenografts. Among these immunosuppressants, clinical applications such as anti-CD40 are already in progress, and anti-CD154 and others are under preclinical primate trials before clinical trials. It is thought that preclinical experimental research on xenografts is playing a forefront role in the development of immunosuppressive agents for allografts.

Initial Human Xenotransplantation

World-first human xenotransplantation with a pig kidney in September 2021

It was reported that a pig kidney was attached to a human patient and the organ function was watched for 54 hours. This was the first time that a pig kidney was transplanted to a human body and was not immediately rejected. The recipient was a brain-dead donor, but her organs were not suitable for donation. A kidney from a genetically engineered pig was attached outside of the human body to assess its function in real-time. The pig’s thymus gland was also transplanted with the kidney to improve its chances of acceptance. Within minutes, the kidney started producing large amounts of urine and showed other signs of normal functioning. The transplant team closely monitored the kidney for 54 hours and saw no signs of rejection [44,45].

World-first human xenotransplantation with a pig heart in January 2022

A 57-year-old male had been on cardiac support for two months and could not receive a mechanical heart pump because of an irregular heartbeat. Neither could he receive a human transplant. Given that he otherwise faced certain death, the researchers got permission from the FDA to transplant a pig heart. To prepare the pig heart for the transplant, the researchers knocked out three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aimed to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized. Ten of those genes in the donor pig had been altered through a time-consuming gene-editing process. The new pig heart was functioning and already doing most of the work; the patient was closely monitored for signs of the new organ rejection, and there was no incident in the first 48 hours, which were critical, passed without incident [46,47]. Two months later, this patient passes away due to pig heart failure of unknown cause [48].

CONCLUSIONS

With the development of CNIs, the outcomes of organ transplantation have improved, especially in immunologically low-risk patients. All new immunosuppressants and regimens should be validated under the considerations for risk-benefit balance in various clinical conditions. Immunosuppressive therapy strategies are needed in the future to effectively control antibodies and antibody-mediated rejection while avoiding CNI-associated complications.

FUNDING

There was no funding related to this study.

CONFLICT OF INTEREST

All authors have no conflicts of interest to declare.

AUTHORS’ CONTRIBUTIONS

Conceptualization: JIP. Data curation: JIP. Methodology: All. Visualization: All. Writing - original draft: All. Writing - review & editing: All.

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The Korean Liver Transplantation Society

Vol.2 No.1
May, 2022

pISSN 2765-5121
eISSN 2765-6098

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