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Current Opinion in Rheumatology Mar 2014To provide an overview of recent advances and future possibilities for therapeutic tolerance. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of recent advances and future possibilities for therapeutic tolerance.
RECENT FINDINGS
Allograft survival despite complete immunosuppressant withdrawal has been demonstrated in selected renal-transplant recipients with haematopoietic chimerism. Early clinical trials of mesenchymal stromal cell therapy have shown promising results in several autoimmune diseases. Regulatory T cells show potential benefit in graft versus host disease, although challenges to ex-vivo expansion remain. Targeted modulation of T-cell function in vivo with monoclonal antibodies has shown beneficial effects in phase II/III trials of multiple sclerosis (alemtuzumab) and type I diabetes mellitus (teplizumab, otelixizumab). Emerging data from animal models suggest an important role for the commensal microbiome in the maintenance and disruption of immune tolerance with parallels in human studies.
SUMMARY
After years of slow progress, recent research has reduced the translational gap between animal models and clinical therapeutic tolerance. Early detection of autoimmunity, potentially at preclinical stages, offers a window of opportunity for tolerogenic therapy. Reliable biomarkers of tolerance are urgently needed to provide objective measurements of the effectiveness of tolerogenic therapies, and to allow intelligent immunosuppressant withdrawal in patients whose autoimmune disease is stable.
VIDEO ABSTRACT AVAILABLE
See the Video Supplementary Digital Content 1 (http://links.lww.com/COR/A8).
Topics: Allografts; Animals; Autoimmune Diseases; Biomarkers; Cell- and Tissue-Based Therapy; Graft Survival; Humans; Immune Tolerance; Immunosuppression Therapy; Microbiota; T-Lymphocytes; Translational Research, Biomedical; Transplantation Chimera; Transplantation Immunology
PubMed: 24378931
DOI: 10.1097/BOR.0000000000000029 -
JACC. Heart Failure Dec 2017
Review
Topics: Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents
PubMed: 29191303
DOI: 10.1016/j.jchf.2017.10.010 -
Transplantation and Cellular Therapy Mar 2023Hematopoietic stem cell transplantation (HSCT) is a curative treatment for patients with many different blood and immune diseases; however, current treatment regimens...
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for patients with many different blood and immune diseases; however, current treatment regimens contain non-specific chemotherapy and/or irradiation conditioning, which carry both short-term and long-term toxicities. The use of such agents may be particularly harmful for patients with Fanconi anemia (FA), who have genetic mutations resulting in deficiencies in DNA repair, leading to increased sensitivity to genotoxic agents. mAb-based conditioning has been proposed as an alternative conditioning strategy for HSCT that minimizes these toxicities by eliminating collateral tissue damage. Given the high need for improved treatments for FA patients, we aimed to evaluate the efficacy of different αCD117 mAb agents and immunosuppression on hematopoietic stem cell (HSC) depletion and explored their ability to safely establish therapeutic donor hematopoiesis post-HSCT in FA disease models. We evaluated the effects of different concentrations of αCD117 mAbs in vitro and in vivo on HSC growth and depletion. To further assess the efficacy of mAb-based conditioning, Fancd2 animals were treated with αCD117 mAb and combination agents with αCD47 mAb and antibody-drug-conjugates (ADCs) for syngeneic HSCT. Immunosuppression αCD4 mAb was added to all in vivo experiments due to a slightly mismatched background between the donor grafts and recipients. Immunosuppressant cocktails were also given to Fancd2 animals to evaluate the efficacy of mAb-based conditioning in the haploidentical setting. Statistical analyses were done using the unpaired t-test. We found that antagonistic αCD117 mAbs alone do not deplete host HSCs or enhance HSCT effectively in FA mouse models; however, the potency of αCD117 mAbs can be safely augmented through combination with αCD47 mAbs and with ADCs, both of which lead to profound HSC depletion and establishment of long-term donor engraftment post-syngeneic HSCT. This is the first time these approaches have been tested in parallel in any disease setting, with the greatest donor engraftment observed after CD117-ADC conditioning. Interestingly, our data also suggest that HSC-targeted conditioning is not necessary in HSCT for FA, as high donor HSC engraftment was observed with mAb-based immune suppression alone with immunologically matched and mismatched haploidentical grafts. These results demonstrate the safety and efficacy of several different non-genotoxic mAb-based conditioning strategies in the FA setting. In addition, they show that if sufficient immunosuppression is given to obtain initial donor HSC engraftment, turnover of a majority of the hematolymphoid system can result, likely owing to the survival advantage of wild-type HSCs over FA HSCs. Such non-toxic all-mAb-based conditioning strategies could be transformative for FA patients and those with other hematolymphoid diseases.
Topics: Animals; Mice; Fanconi Anemia; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Immunosuppressive Agents; Immunosuppression Therapy; Antibodies, Monoclonal
PubMed: 35995393
DOI: 10.1016/j.jtct.2022.08.015 -
Nature Communications Apr 2024Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman...
Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.
Topics: Animals; Humans; Swine; Transplantation, Heterologous; Graft Survival; Heterografts; Kidney; Immunosuppression Therapy; CD40 Ligand; CD40 Antigens; Graft Rejection
PubMed: 38637524
DOI: 10.1038/s41467-024-47679-6 -
Postepy Higieny I Medycyny... Dec 2015Immunosuppression is a condition characterized by weakened or inhibited immune response. It occurred both in humoral and cellular response. This is related to the... (Review)
Review
Immunosuppression is a condition characterized by weakened or inhibited immune response. It occurred both in humoral and cellular response. This is related to the variable levels of deficiency for each antibody class (IgG, IgM, IgA) and a decrease in the number and function of immune cells, mainly T cells which results in the inhibition of cytokine production, signaling transduction and clonal expansion. Immunosuppressive therapy is used in many fields of medicine, such as transplantology, oncology, autoimmune disorders. Immunosuppression can be induced in several ways, by the surgical resection of the organs of the immune system, physical methods using X-rays or chemical methods using pharmacological agents. The most common way to induce immunosuppression is the administration of immunosuppressive drugs, amongst others: glucocorticoids, cytostatic drugs, immunophilin-binding agents, monoclonal antibodies. Unfortunately, the desired therapeutic effects of immunosuppression may be accompanied by a number of side effects associated with both impaired immunity (susceptibility to infections, including those caused by opportunistic microorganisms), toxic effects on the tissues (nephrotoxicity, neurotoxicity), or with a direct impact on the processes of malignancy. This harmful influence can be limited by the modification of the existing drugs, looking for new ones or developing new methods for the controlled kinetics of releasing the immunosuppressive pharmaceuticals. The personalization of immunosuppressant treatment according to genetic/genomic characteristics of individual patient represents the quite innovative look into the issue of immunosuppression.
Topics: Autoimmune Diseases; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Neoplasms; Precision Medicine; Transplantation; X-Rays
PubMed: 26671921
DOI: 10.5604/17322693.1184554 -
Hematology. American Society of... Dec 2016Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be... (Review)
Review
Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.
Topics: Anemia, Aplastic; Anemia, Refractory; Benzoates; Danazol; Humans; Hydrazines; Immunosuppression Therapy; Pyrazoles
PubMed: 27913466
DOI: 10.1182/asheducation-2016.1.83 -
BMJ (Clinical Research Ed.) Jun 1992
Topics: Graft Rejection; Humans; Immunosuppression Therapy; Intestine, Small; Liver Transplantation; Research
PubMed: 1611363
DOI: 10.1136/bmj.304.6840.1453 -
Liver Transplantation : Official... Aug 2001
Topics: Humans; Immunosuppression Therapy; Organ Transplantation; Steroids
PubMed: 11510014
DOI: 10.1053/jlts.2001.27232 -
International Journal of Molecular... Jan 2023The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss.... (Review)
Review
The clinical success of solid organ transplantation is still limited by the insufficiency of immunosuppressive regimens to control chronic rejection and late graft loss. Moreover, serious side effects caused by chronic immunosuppressive treatment increase morbidity and mortality in transplant patients. Regulatory T cells (Tregs) have proven to be efficient in the induction of allograft tolerance and prolongation of graft survival in numerous preclinical models, and treatment has now moved to the clinics. The results of the first Treg-based clinical trials seem promising, proving the feasibility and safety of Treg therapy in clinical organ transplantation. However, many questions regarding Treg phenotype, optimum dosage, antigen-specificity, adjunct immunosuppressants and efficacy remain open. This review summarizes the results of the first Treg-based clinical trials for tolerance induction in solid organ transplantation and recapitulates what we have learnt so far and which questions need to be resolved before Treg therapy can become part of daily clinical practice. In addition, we discuss new strategies being developed for induction of donor-specific tolerance in solid organ transplantation with the clinical aims of prolonged graft survival and minimization of immunosuppression.
Topics: T-Lymphocytes, Regulatory; Graft Rejection; Immune Tolerance; Organ Transplantation; Immunosuppression Therapy; Transplantation Tolerance; Immunosuppressive Agents
PubMed: 36675265
DOI: 10.3390/ijms24021752 -
Journal of Plastic, Reconstructive &... Dec 2023Since the first procedure performed in 2005, face transplantation has been debated as viable approach for the treatment of severe craniofacial defects. Despite the... (Review)
Review
BACKGROUND
Since the first procedure performed in 2005, face transplantation has been debated as viable approach for the treatment of severe craniofacial defects. Despite the benefits provided, the experience in face allotransplantation has brought to light a significant risk of complications, including allograft removal or loss, and mortality. The present study is intended to provide an updated review on complications and major challenges witnessed over 18 years of experience in the field.
METHODS
A systematic review of PubMed, MEDLINE, Cochrane, Google, and Google Scholar databases on face transplantation was conducted according to PRISMA guidelines up to April 2023. Articles providing details on cases of face allograft loss, removal, and patient death were included. Online articles and media reports were assessed to include information not disclosed in peer-reviewed literature. Face transplant centers were contacted to have updated follow-up information on single-face transplant cases.
RESULTS
The search yielded 1006 reports, of which 28 were included. On a total of 48 procedures performed in 46 patients, adverse outcomes were gleaned in 14 cases (29%), including seven allograft losses (14.6%), and the death of ten patients (21.7%). Chronic rejection was the leading cause of allograft loss, with a median time from transplant to irreversible rejection of 90 months (IQR 88.5-102). The main causes of death were infectious complications, followed by malignancies, non-compliance to immunosuppression, and suicide. The median time to death was 48.5 months (IQR 19-122).
CONCLUSIONS
To the best of our knowledge, this is the first study providing a comprehensive review of adverse outcomes in face transplantation. Considering the high rate of major complications, the heterogeneity of cases and single-center approaches, and the absence of published standards of care, the development of a consensus by face transplant teams holds the key to the field's advancement.
Topics: Humans; Facial Transplantation; Immunosuppression Therapy; Immune Tolerance; Graft Rejection
PubMed: 37879143
DOI: 10.1016/j.bjps.2023.09.043