-
EBioMedicine Dec 2022Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ... (Review)
Review
Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, this definition belies the complexity and breadth of immune mechanisms involved in sepsis, which are characterized by simultaneous hyperinflammation and immune suppression. In this review, we describe the immunopathogenesis of sepsis and highlight some recent pathophysiological findings that have expanded our understanding of sepsis. Sepsis endotypes can be used to divide sepsis patients in different groups with distinct immune profiles and outcomes. We also summarize evidence on the role of the gut microbiome in sepsis immunity. The challenge of the coming years will be to translate our increasing knowledge about the molecular mechanisms underlying sepsis into therapies that improve relevant patient outcomes.
Topics: Humans; Sepsis; Immunosuppression Therapy; Gastrointestinal Microbiome
PubMed: 36470832
DOI: 10.1016/j.ebiom.2022.104363 -
Best Practice & Research. Clinical... 2020The increasing potency of immunosuppression (IS) agents resulted in significantly decreased rates of steroid resistant rejection and rejection related graft loss in... (Review)
Review
The increasing potency of immunosuppression (IS) agents resulted in significantly decreased rates of steroid resistant rejection and rejection related graft loss in liver transplantation (LT). Currently, more than two thirds of late mortality after LT is unrelated to graft function. However, the increased benefit of more potent IS drugs, coupled with the prolonged survival of transplant recipients led to longer patients exposure to these drugs and their unwanted adverse effects, creating a double-edged sword. In this article the authors describe the mechanism of action and the adverse effects of the most commonly used immunosuppressed drugs, and the most commonly used IS regimens for both induction and maintenance regimens. The balance between the ideal IS regimen to prevent rejection and the need to minimize the dose of IS drugs in order to prevent the adverse effects related to its use requires the knowledge of the science and the experience with the art of medicine. The different protocols aimed at protecting renal function and preventing the development of de novo cancer and metabolic syndrome are discussed here. The main causes of mortality late after liver transplant are associated with prolonged use of IS medications, and clear evidence exists about over-immunosuppression of recipients of liver transplant. The current status of strategies of IS minimization and withdrawal are reviewed in this article, with evaluation of its benefits and pitfalls.
Topics: Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation
PubMed: 33158467
DOI: 10.1016/j.bpg.2020.101681 -
Nature Reviews. Nephrology Sep 2018The human major histocompatibility complex is a family of genes that encodes HLAs, which have a crucial role in defence against foreign pathogens and immune surveillance... (Review)
Review
The human major histocompatibility complex is a family of genes that encodes HLAs, which have a crucial role in defence against foreign pathogens and immune surveillance of tumours. In the context of transplantation, HLA molecules are polymorphic antigens that comprise an immunodominant alloreactive trigger for the immune response, resulting in rejection. Remarkable advances in knowledge and technology in the field of immunogenetics have considerably enhanced the safety of transplantation. However, access to transplantation among individuals who have become sensitized as a result of previous exposure to alloantigens is reduced proportional to the breadth of their sensitization. New approaches for crossing the HLA barrier in transplantation using plasmapheresis, intravenous immunoglobulin and kidney paired donation have been made possible by the relative ease with which even low levels of anti-HLA antibodies can now be detected and tracked. The development of novel protocols for the induction of tolerance and new approaches to immunomodulation was also facilitated by advances in HLA technology. Here, we review the progress made in understanding HLAs that has enabled organ transplantation to become a life-saving endeavour that is accessible even for sensitized patients. We also discuss novel approaches to desensitization, immunomodulation and tolerance induction that have the potential to further improve transplantation access and outcomes.
Topics: Adaptive Immunity; Desensitization, Immunologic; Graft Rejection; HLA Antigens; Histocompatibility Testing; Humans; Immune Tolerance; Immunosuppression Therapy; Kidney Transplantation
PubMed: 29985463
DOI: 10.1038/s41581-018-0039-x -
Clinical Infectious Diseases : An... Oct 2021Successful solid organ transplantation reflects meticulous attention to the details of immunosuppression, balancing risks for graft rejection against risks for... (Review)
Review
Successful solid organ transplantation reflects meticulous attention to the details of immunosuppression, balancing risks for graft rejection against risks for infection. The "net state of immune suppression" is a conceptual framework of all factors contributing to infectious risk. Assays that measure immune function in the immunosuppressed transplant recipient relative to infectious risk and allograft function are lacking. The best measures of integrated immune function may be quantitative viral loads to assess the individual's ability to control latent viral infections. Few studies address adjustment of immunosuppression during active infections; thus, confronted with infection in solid organ recipients, the management of immunosuppression is based largely on clinical experience. This review examines known measures of immune function and the immunologic effects of common immunosuppressive drugs and available studies reporting modification of drug regimens for specific infections. These data provide a conceptual framework for the management of immunosuppression during infection in organ recipients.
Topics: Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Organ Transplantation
PubMed: 32803228
DOI: 10.1093/cid/ciaa1189 -
The New England Journal of Medicine Aug 2021
Review
Topics: Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Survival Rate
PubMed: 34407344
DOI: 10.1056/NEJMra2014530 -
Blood Jan 2015Chronic graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The... (Review)
Review
Chronic graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The 2-year cumulative incidence of chronic GVHD requiring systemic treatment is ~30% to 40% by National Institutes of Health criteria. The risk of chronic GVHD is higher and the duration of treatment is longer after HCT with mobilized blood cells than with marrow cells. Clinical manifestations can impair activities of daily living and often linger for years. Hematology and oncology specialists who refer patients to centers for HCT are often subsequently involved in the management of chronic GVHD when patients return to their care after HCT. Treatment of these patients can be optimized under shared care arrangements that enable referring physicians to manage long-term administration of immunosuppressive medications and supportive care with guidance from transplant center experts. Keys to successful collaborative management include early recognition in making the diagnosis of chronic GVHD, comprehensive evaluation at the onset and periodically during the course of the disease, prompt institution of systemic and topical treatment, appropriate monitoring of the response, calibration of treatment intensity over time in order to avoid overtreatment or undertreatment, and the use of supportive care to prevent complications and disability.
Topics: Allografts; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Incidence; Male
PubMed: 25398933
DOI: 10.1182/blood-2014-08-551994 -
Blood Mar 2017Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells... (Review)
Review
Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells plays an important role in pathogenesis, as shown by successful treatment with immunosuppressive agents, leading to transfusion independence or complete recovery of peripheral blood counts in a proportion of patients. Growth factors can be combined with immunosuppressive therapy (IST) and may improve response rates, as recently shown with thrombopoietin analogs. Anabolic steroids may still play a role in combination with IST. The problem with IST is failure to respond and the development of late clonal disorders. Bone marrow transplantation (BMT) is the other therapeutic option: a matched sibling donor remains the best choice. For patients lacking a matched family donor, unrelated donors can be readily found, although mostly for patients of Caucasian origin. Other BMT options include unrelated cord blood or mismatched family donors. Acute and chronic graft-versus-host disease remain important complications of BMT. Patient age is a strong predictor of outcome for both IST and BMT, and must be considered when designing therapeutic strategies. Early diagnosis and treatment, as well as long-term monitoring, remain crucial steps for successful treatment of SAA.
Topics: Anemia, Aplastic; Bone Marrow Transplantation; Humans; Immunosuppression Therapy; Treatment Outcome
PubMed: 28096088
DOI: 10.1182/blood-2016-08-693481 -
Clinical Microbiology Reviews Jun 2020The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as... (Review)
Review
The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.
Topics: Biological Products; Humans; Immunomodulation; Immunosuppression Therapy; Opportunistic Infections; Risk Factors
PubMed: 32522746
DOI: 10.1128/CMR.00035-19 -
Current Opinion in Ophthalmology Jul 2017Keratolimbal allograft (KLAL) transplants limbal tissue attached to a corneoscleral carrier from a cadaveric donor to deliver a large number of stem cells to the... (Review)
Review
PURPOSE OF REVIEW
Keratolimbal allograft (KLAL) transplants limbal tissue attached to a corneoscleral carrier from a cadaveric donor to deliver a large number of stem cells to the recipient. The present article will provide a review of KLAL focusing on the recent literature.
RECENT FINDINGS
Recent findings pertain to tissue selection, immunosuppression and adverse event profiles, and postoperative complications (particularly related to immunologic rejection).
SUMMARY
KLAL permits the treatment of limbal stem cell deficiency eyes when there is no available living-related or autograft tissue with minimal risk of irreversible toxicity from modern systemic immunosuppression. The prevention of immunologic graft rejection with the use of systemic immunosuppression after KLAL is critical and may require extending systemic immunosuppression treatment longer than previously thought. With vigilant postoperative management, KLAL can allow successful treatment of the most severely diseased eyes.
Topics: Corneal Diseases; Epithelial Cells; Graft Rejection; Humans; Immunosuppression Therapy; Limbus Corneae; Postoperative Complications; Sclera; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 28379858
DOI: 10.1097/ICU.0000000000000374 -
Ophthalmology Feb 2018The uveitides are a collection of more than 30 diseases characterized by intraocular inflammation. Many cases of juvenile idiopathic arthritis-associated uveitis, many... (Review)
Review
The uveitides are a collection of more than 30 diseases characterized by intraocular inflammation. Many cases of juvenile idiopathic arthritis-associated uveitis, many cases of intermediate uveitis, and most cases of posterior and panuveitides requiring treatment are treated with corticosteroids and immunosuppression. Disease-specific, time-updated modeling of clinical data for several uveitides suggests superior prevention of ocular complications and visual outcomes with immunosuppression. These studies also suggest that oral corticosteroids at doses low enough for safe long-term therapy (i.e., <7.5 mg/day) are ineffective, implying that immunosuppression should be part of the initial regimen. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study was a randomized comparative effectiveness trial comparing systemic therapy with oral corticosteroids and immunosuppression with regional corticosteroid treatment. It demonstrated that, when used properly, oral corticosteroids and immunosuppression can be given safely for up to 7 years with no evident increased risk of systemic side effects compared with regional corticosteroid therapy, except for greater antibiotic use for infections. The Systemic Treatment for Eye Diseases (SITE) Cohort Study suggested long-term safety for this approach, when the immunosuppressive agents were antimetabolites or calcineurin inhibitors. Thus, oral corticosteroids and immunosuppression may be a preferred initial therapy for many noninfectious, intermediate, posterior, and panuveitides. Nonalkylating-agent immunosuppression has a low rate of sustained, drug-free remissions, <10%/year. Nonalkylating-agent immunosuppression for >3 years with control of the inflammation for >2 years is associated with a decreased risk of relapse after discontinuing immunosuppression. Alkylating agents can induce sustained drug-free remissions but likely increase the lifetime risk of cancer. Biologics, which target specific cytokines and pathways, hold promise for the future. Monoclonal antibodies directed against tumor necrosis factor (TNF)-α have been studied most often, and one, adalimumab, is U.S. Food and Drug Administration approved for the treatment of noninfectious, intermediate, posterior, and panuveitides.
Topics: Humans; Immunosuppression Therapy; Immunosuppressive Agents; Uveitis; Visual Acuity
PubMed: 28942074
DOI: 10.1016/j.ophtha.2017.08.007