Immunobiology Of Transplantation Research Articles

IFN-GAMMA MODULATED FAST-DENDRITIC CELLS PROMOTE THE GENERATION OF CD4+CD25+FOXP3HI T-REGULATORY CELLS: A POTENTIAL THERAPY FOR CLINICAL ISLET ALLOTRANSPLANTATION

1Salisbury/South Australia/AUSTRALIA, 2Central Northern Adelaide Renal And Transplantation Services, Renal And Transplantation Immunobiology Laboratory, The Royal Adelaide Hospital, Adelaide/SA/AUSTRALIA, 3Central Northern Adelaide Renal And Transplantation Service, Royal Adelaide Hospital, Adelaide/AUSTRALIA

The immunobiology of cord blood transplantation

Despite significant recent advances in the applicability and outcome following unrelated cord blood transplantation (UCBT), infections remain a major cause of mortality associated with poor immune recovery in the first 6 months after UCBT. Enhanced immune reconstitution not only could improve survival by reduced transplant related mortality, but may also favorably impact on relapse incidence by improved graft-versus-leukemia effects. This review will summarize our current understanding of the biology of immune recovery post-UCBT with an emphasis on adaptive T cell dependent immunity. New efforts to boost immunity will be also highlighted including our own laboratory, where ex vivo T cell expansion is pursued towards adoptive immunotherapy.

EBMT Göteborg 29 March–1 April 2009: inborn error and transplantation immunobiology minutes

This report includes highlights of sessions on haematopoietic stem cell transplantation (HSCT) and other immunologic treatment options for patients with inherited metabolic disorders, autoimmune diseases, immunodeficiencies and few other main topics of the 2009 annual EBMT meeting. Although chosen for their relevance for paediatricians working in the fields of haematology/oncology, immunology and inborn errors of metabolism, due to the occurrence of multiple parallel lectures, this article may only touch a selection of main topics and does not claim to be a complete conference report. Citations of the discussed conference papers are referred to by their presentation number as indicated within the congress abstract book, the Supplemental issue of Bone Marrow Transplantation Volume 43 S1 [1]. A separate report on the EBMT Paediatric Diseases Working Party is presented in this issue of memo [2].

Immunobiology of Bone Marrow Transplantation

Acta Medica ScandinavicaVolume 209, Issue 1-6 p. 10-10 Immunobiology of Bone Marrow Transplantation Gösta Gahrton, Gösta Gahrton Huddinge, SwedenSearch for more papers by this author Gösta Gahrton, Gösta Gahrton Huddinge, SwedenSearch for more papers by this author First published: January/December 1981 https://doi.org/10.1111/j.0954-6820.1981.tb11543.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume209, Issue1-6January/December 1981Pages 10-10 RelatedInformation

Transplantation immunobiology: two important themes

Organ transplantation has become the method of choice for the treatment of many diseases because of advances in both surgical and immunosuppressive techniques. These techniques have now progressed to the stage where satisfactory graft acceptance and survival can be achieved by the judicious choice of donor and recipient, and by the appropriate patient management. As a result of the improved quality of life of transplant recipients, an ever-increasing number of potential recipients are being added to the waiting lists. Despite the success of clinical transplantation, two key challenges for the field are (1) the dwindling number of suitable donors and (2)the adverse effects and the risks of long-term administration of immunosuppressive drugs. It is a well-established fact that the supply of organs for transplantation is not only inadequate but also worsening globally. Although education programs and various legal changes may increase the availability of donors, it is unlikely to solve the problem completely. The potential solutions being examined include the use of artificial organs, stem cells to engineer organs and tissues and xenotransplantation. Even though the first two options are appealing and shows potential, xenotransplantation is closest to clinical applications. The proposed use of pig organs for xenotransplantation has reintroduced the problem of hyperacute rejection, which results in the antibody-mediated destruction of a vascularized pig organ within minutes because of natural preformed antibodies. The expression of human complement regulators, either alone, or in combination, was initially used in an attempt to protect the xenograft. Several human complement regulators extended the survival of pig organs in primate transplant models from minutes or hours to days in unmodified recipients, and was further increased to 5 months with intense immunosuppression. A significant step for the field was not only the identification of the carbohydrate antigen recognized by naturally occurring human antibodies but, more importantly, the generation of homozygous pigs with a disruption in the gene that encodes the enzyme, α1,3galactosyltransferase. Using these Gal knockouts for pig-to-primate vascularized organ transplants, again using clinically inappropriate immunosuppression, showed survival times similar to those observed in the pigs expressing human complement regulators. Therefore, although inactivation of the α1,3galactosyltransferase gene prevents hyperacute rejection of vascularized organs, they still succumb to acute vascular rejection as a consequence of antibodies (natural or elicited) binding to and activating endothelial cells, or unidentified cross-species molecular incompatibilities. For transplantation, the major side effects of long-term immunosuppression are infection and malignancy. A major goal in transplantation for many years has been the induction of ‘transplant tolerance’—the long-term acceptance of the transplant with the maintenance of responses to nondonor antigens (such as viruses) without the need for chronic immunosuppression. This has involved immunological manipulations to re-educate the immune system to establish transplant tolerance and allow permanent survival of the graft. Despite continuing research in this area and success in small animal models, clinical tolerance remains elusive. Recently, interest has been renewed in the subsets of T cells, notably regulatory T cells (Tregs) and their potential role in tolerance induction. These Tregs can be identified by their expression of CD4, CD25 and the transcription factor, Foxp3. Foxp3 is currently the single best marker available for identifying Tregs, with stable expression of Foxp3, and is regarded as the ‘master switch’ for Treg function. For clinical transplantation, the ability to harness the potential of allograft-specific Treg cells would reduce the need for nonspecific immunosuppressive therapy currently required to prevent graft rejection, and may be a critical step toward inducing donor-specific tolerance and permanent graft survival. The following two Special Feature Reviews, which are contributions from the State of the Art Symposia at the recent Sydney Congress of the Transplantation Society, address progress made in these two areas: a review by Cowan and d’Apice on the current state of the field of xenotransplantation focusing on the complement and coagulation systems and their roles in vascular injury; and a review by Wang et al. on the role of histone deacetylases and their inhibitors on the generation of Foxp3+ Tregs with particular emphasis on transplantation tolerance induction. By a combination of both these approaches in the future, it is feasible that the dual problems of organ availability and long-term side effects of immunosuppression may be solved.

NK CELL STIMULATORY RECEPTORS AND LIGANDS ARE INDUCED IN LIVER ALLOGRAFTS EARLY POST- TRANSPLANTATION

Transplant Immunobiology Lab, Division of Transplantation, Department of Surgery, Stanford University

Graft failure IV. Immunologic mechanisms of corneal transplant rejection

Corneal transplantation is the oldest and the most common form of solid tissue transplantation in humans. Immunologic graft rejection is one of the main causes of short and long-term graft failure. Rejection involves donor tissue recognition and destruction by allo-specific immune cells of the recipient. This review outlines (1) the immunobiology of transplantation, with reference to ocular immune privilege, (2) factors that confer "high-risk" status to a graft and (3) the pathophysiologic mechanisms of corneal transplant rejection.

Technique of kidney transplantation in mice with anti-reflux urinary reconstruction

Experimental models of organ transplantation play a crucial role in establishing the principles of transplantation immunobiology. Murine transplant models of vascularized organs are particularly useful for immunobiological studies because there are more immunological tools available. However, the technique of kidney transplant in mice is very challenging. A difficult aspect of this model is urinary reconstruction, which is frequently associated to complications. In this article, the technique of mouse kidney transplantation using an anti-reflux system (modified extravesical ureteroneocystostomy) is described and illustrated for the first time. Although technically demanding, this procedure is feasible and may reduce the incidence of urine leakage and reflux.

The Immunobiology of Transplantation. By Rupert Billingham and Willys Silvers, University of Pennsylvania. 9 × 5¾ in. Pp. 209 + xiii. Illustrated. 1971. London: Prentice-Hall International Inc. £2

The Immunobiology of Transplantation. By Rupert Billingham and Willys Silvers, University of Pennsylvania. 9 × 5¾ in. Pp. 209 + xiii. Illustrated. 1971. London: Prentice-Hall International Inc. £2

Engraftment of human T, B and NK cells in CB.17 SCID/beige mice by transfer of human spleen cells

Models of severe combined immuno-deficient (SCID) mice reconstituted with a competent human immune system represent a valuable tool for the study of human immune responses in vivo. Reconstitution with human cells can be achieved using large numbers of peripheral blood lymphocytes, but levels of engraftment are poor and graft versus host disease (GVHD) frequently occurs. SCID/beige mice are at the same time deficient for adaptive and innate immunity and the objective of this study was to develop a safe and efficient way to achieve human lymphocyte engraftment in these mice using human spleen cells. After institutional authorisations and informed consent of relatives, a piece of spleen was obtained from cadaveric organ donors and the splenocytes were isolated and cryopreserved for later use. Single intraperitoneal injections of 5–100 × 10 6 splenocytes were performed into SCID/beige mice. Reconstitution of a human immune system was monitored weekly by the presence of human cells and IgG in peripheral blood. The mice were sacrificed 4 weeks after the injection and the engraftment in lymphoid organs was studied. A reproducible reconstitution was obtained with intraperitoneal injection of 30–40 × 10 6 spleen cells. Human T, B and NK cells as well as human IgG were present in peripheral blood. In lymphoid tissues, the same lymphocytic subpopulations were detected and in addition some antigen presenting cells. The reconstitution was functional because graft rejection was observed after transplantation of human allogeneic tissues. When less than 30 × 10 6 cells were injected, the reconstitution was variable. When more than 40 × 10 6 cells were injected, GVHD occurred with increasing frequency. In conclusion, we show that intraperitoneal injection of 30–40 × 10 6 human splenocytes into SCID/beige mice induces a quick and functional engraftment of human T, B and NK cells with no risk of GVHD. This model may be used to study human transplantation immunobiology in vivo.

A Novel Immunocompetent Rat Model of HCV Infection and Hepatitis

Hepatitis C virus (HCV) infects millions of people worldwide. Therapy is limited, and treatment does not produce a sustained response in the majority of patients. Development of new agents has been hampered by the lack of a convenient animal model. The aim of this study was to determine whether an immunocompetent rat, tolerized and transplanted with a human hepatoma cell line (Huh 7 cells), could be used to sustain an HCV infection. Fetal rats were tolerized in utero with 10(5) Huh 7 cells. One day after birth, rats were transplanted with 5 x 10(6) Huh 7 cells and, a week later, inoculated with HCV, genotype 1. In tolerized, transplanted, and HCV-infected rats, Huh 7 cells were found in the liver, and HCV viral replication was detected by the presence of negative strand HCV RNA. HCV levels in serum were measured at 11,000 copies/mL at week 4, peaked at 22,500 copies/mL by week 12. In tolerized, transplanted, inoculated rats, but not controls, serum alanine aminotransferase (ALT) values increased to 60 IU/L by week 4 and reached a peak of approximately 120 IU/L by week 13. Histology showed foci of mononuclear infiltrates in portal and central regions. HCV-inoculated immunocompetent rats tolerized and transplanted with Huh 7 cells support HCV gene expression, viral replication, and develop biochemical and histologic evidence of hepatitis.

Effects of a Tolerance Induction Protocol in Renal Allograft Recipients — the Ahmedabad Experience

The most interesting recent development in transplantation immunobiology is the clinical implementation of tolerance induction. We report our experience of megadose hematopoietic stem cell transplantation with non-myeloablative minimum conditioning in renal allograft recipients. This was a retrospective, single-center study of 159 renal allograft biopsies from two groups of patients: one group underwent a tolerance induction protocol (TIP) before renal transplantation; the other underwent renal transplantation directly. Biopsies were classified into two subgroups to differentiate between acute and late rejection: 127 biopsies, comprising 64 from patients who underwent a TIP and 63 from controls, performed within 180 days after transplantation; and 32 biopsies, comprising 26 from patients who underwent a TIP and six from controls, performed 180 days after transplantation. All patients received cyclosporine 7 mg/kg/day, tapered to 3 mg/kg/day 3 months after transplantation, and subsequently continued at the latter dosage. There was markedly less immunologic injury (i.e. generally fewer and milder rejection episodes) evident in biopsies from patients who underwent TIP than in biopsies from controls. Cyclosporine toxicity was considerably greater in patients from the TIP versus control group (82.9% vs 40.6%). TIP protects renal allografts from immunologic injury and has an unexplained cyclosporine-sparing effect.

Bioluminescence Imaging of Pancreatic Islet Transplants

Bioluminescence imaging (BLI) modalities have been developed, refined, and used broadly in the study of small animal models of human biology and disease. Here, we review the importance of developing an in vivo imaging modality for real-time monitoring islets post transplantation. In order to advance our understanding of the pathophysiology and immunobiology of islet transplantation as they occur in living animals, islet grafts tagged with lightemitting luciferase can be implanted in a mouse islet transplantation model and assessed using in vivo BLI. Some of the preliminary data, considerations of using the system, and future applications of BLI in the field of islet transplantation research are discussed. Keywords: bioluminescence, imaging, islet transplantation, in vivo, transgenic mice, luciferase, luciferin

Transplant: immunology and treatment of rejection

Transplant: immunology and treatment of rejection

Respecting Patients' Rights in Manuscripts: Confidentiality, Informed Consent, and IRB Approval

Patients' rights for privacy and confidentiality extend to publications. This author describes how authors, reviewers, and editors can ensure patient confidentiality in manuscripts.

Acceptance of islet allografts in the liver of mice by blockade of an inducible costimulator.

An inducible costimulator (ICOS) has been found to be a novel costimulator for T-cell activation, although its precise role in transplant immunobiology remains unclear. This study determined whether ICOS plays an essential role in rejection of intrahepatic islet allografts in streptozotocin-induced diabetic mice. Mononuclear cells in the liver of mice were isolated and examined by flow cytometry with respect to expression of ICOS in association with rejection, and the effects of in vivo treatment with an anti-ICOS antibody on survival of intrahepatic islet allografts were determined. RESULTSFlow cytometric analysis of mononuclear cells in the liver of normal untreated mice revealed that ICOS is expressed on CD4+CD3int natural killer T cells. The expression of ICOS was up-regulated on CD4+CD3bright T cells and expanded CD8 T cells in the liver in association with rejection. Posttransplant short-term administration of anti-ICOS antibody alone produced a significant prolongation of islet allograft survival. Administration of the antibody in conjunction with a subtherapeutic regimen of FK506 prevented rejection, leading to the acceptance of islet allografts. ICOS has an essential role in rejection of intrahepatic islet allografts and the blockade of ICOS interaction might be a novel approach for preventing islet allograft rejection.

STEALTH in transplantation tolerance.

Although contemporary immunosuppressive regimens are responsible for major improvements in allograft acceptance, there are indications that long-term survival may be compromised through drug toxicity and/or chronic immune deficiency. The ultimate goal for transplantation is tolerance, defined as durable, donor-specific allograft acceptance in the absence of long-term immunosuppression. This article reviews the nonhuman primate STEALTH model of tolerance recently developed by the transplant immunobiology group at University of Alabama at Birmingham. The STEALTH model was designed for future application to human transplantation and comprises a concise peritransplant treatment strategy of only 2 wk. Tolerance is induced by depletion of T cells, with concomitant inhibition of nuclear factor-kappaB/RelB-dependent proinflammatory signaling. This treatment has resulted in an unprecedented frequency of kidney allograft survival (62.5% at 3 yr), with some primate recipients remaining in good health more than 6 yr posttransplant, in the complete absence of chronic pharmacologic immunosuppression.

Immunobiology of natural killer cells and bone marrow transplantation: merging of basic and preclinical studies.

Natural killer (NK) cells mediate acute rejection of bone marrow, but not solid tissue, allografts in lethally irradiated mice. Precisely how and why this rejection occurs is still unclear. In allogeneic bone marrow transplantation (BMT), a spectrum of results is possible; one result can be marrow graft failure due to host rejection of the graft by NK and T cells and, at the opposite spectrum, the occurrence of graft-versus-host disease (GVHD). Donor NK cells, however, appear capable of improving donor engraftment without giving rise to GVHD and thus may be of use as an immunotherapy following BMT. As NK-cell inhibitory receptors play a role in bone marrow cell rejection, these same inhibitory receptors may also affect NK responses towards tumor cells. It has been demonstrated that blocking the interaction of inhibitory receptors with MHC determinants on tumor cells can result in greater antitumor effects. Thus, NK cells are capable of mediating both positive and negative effects during BMT depending on whether they are of host versus donor origin and their state of activation. Understanding their role in BMT provides insights as to their physiological roles and points the way to potential clinical uses.

Patterns of engraftment in different strains of immunodeficient mice reconstituted with human peripheral blood lymphocytes.

Models of immunodeficient mice reconstituted with a competent human immune system would represent an invaluable tool for the study of transplantation immunobiology allergy, autoimmunity, and infectious diseases. Severe combined immune deficiency (scid) mice can be successfully reconstituted with human peripheral blood lymphocytes (PBLs), but rates and levels of engraftment are poor. New strains of mice with diverse immunodeficiencies have been recently characterized or developed, which might prove to be advantageous for in vivo studies of human immune reactivity. We have compared rates and patterns of human PBL engraftment in four available immunodeficient murine strains; scid-beige, nonobese diabetic (NOD)-scid, NOD-scid-beta2 m- and rag-. T- and B-lymphocyte engraftment, phenotype of engrafted cells, and occurrence of graft-versus-host disease (GVHD) were studied and compared. Successful engraftment of human PBL was readily obtained in the majority of scid-beige, NOD-scid, and NOD-scid-beta2 m- with a single i.p. administration of human PBLs, whereas it was seldom achieved in rag- animals. Human Ig levels were accordingly remarkably low in rag- recipients but, interestingly also in NOD-scid-beta2 m- mice. Engraftment was readily observed not only in peripheral blood but also in spleen and bone marrow of successfully reconstituted animals. Phenotypic analysis of engrafted human cells showed preserved CD4/CD8 ratios and a clear skewing toward an activated phenotype. GVHD was invariably observed in successfully reconstituted animals. Our data indicate that a high rate of reconstitution with human lymphocytes can be achieved in scid-beige, NOD-scid, and NOD-scid-beta2 m- mice. Human Ig are produced at high levels, except in NOD-scid-beta2 m-, including xenoreactive natural antibodies. Scid-beige and NOD-scid appear therefore better suited than NOD-scid-beta2 m- or rag- for analysis of human immunoreactivity in vivo. An important caveat is the invariable occurrence of GVHD that precludes long-term studies in this model system.

Transplant Immunobiology – Mechanisims of Graft Rejection

Graft rejection is a complex process involving the interplay between innate and adaptive immunity. Many factors including the nature of the tissue transplanted, donor factors, the ischaemia time, the genetic disparities between the donor and recipient, the site of transplantation, and the immune status of the recipient as well as others all contribute to determining the character of the rejection response. Donor derived passenger leukocytes, immature dendritic cells, are present within solid organ grafts at the time of transplantation. These cells are triggered to migrate out of the graft as a result of the inflammation caused by removing the organ from the donor and transplanting it into the recipient. When the donor passenger cells migrate from the graft to the recipient lymphoid tissue they change their functional properties, including the acquisition of costimulatory molecules, and become potent antigen presenting cells (APC). As a result T cells recognizing the mismatched donor major histocompatibility antigens will be activated thereby triggering acute rejection via the direct pathway of allorecognition. Donor histocompatibility antigens can also be recognized by T cells after processing and presentation by recipient antigen presenting cells. This pathway of allorecognition, the indirect pathway, can also be responsible for acute rejection but has also been shown to play a key role in the development of transplant arteriosclerosis that results in delayed graft loss, often referred to as chronic allograft rejection. In general, activation of CD4+ T cells leads to the orchestration of the effector mechanisms that lead to graft destruction. CD8+ T cells with cytotoxic activity, macrophages, antibody and complement and cytokines have all been implicated in the graft destruction. The precise combination of effector cells and their relative contributions to the destruction of a particular graft will depend on the circumstances that have lead to the initiation of the response.