Current opinion in organ transplantation [journal]
- Non-human leukocyte antigen-specific antibodies in thoracic transplantation. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):350-4.
Development of donor human leukocyte antigen (HLA)-specific antibodies is associated with graft loss, yet the role of non-HLA antibodies in solid organ transplant needs to be further defined. It is suggested that HLA antibodies and non-HLA antibodies collaborate together to impact graft outcome. This review focuses on the latest findings on antibodies against these non-HLA antigens in thoracic organ transplant.These non-HLA antigens include signaling proteins expressed on the cell surface, such as angiotensin II type 1 receptor (AT1R), endothelin type A receptor, and structure proteins, such as myosin, vimentin, and Kα1 tubulin, and extracellular matrix protein collagen. Antibodies against these antigens may impact the allograft in different ways. Although these non-HLA antibodies can damage the allograft through complement-mediated or cell-mediated cytotoxicity, antibodies against AT1R and endothelin type A receptor can also alter the endothelial cell function by activating intracellular signals. The presence of these non-HLA antibodies may predispose the patient to develop HLA-specific antibodies. Recently, it has been shown patients with AT1R antibodies pretransplant have a higher chance to develop de-novo donor-specific HLA antibodies.The findings suggest it is important to stratify the patient's immunologic risk by assessing both the HLA and non-HLA-specific antibodies.
- Editorial introductions. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):v-vi.
- The blurring frontier between autoimmunity and alloimmunity. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):349.
- Biomarkers in pancreas transplant. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):412-8.
The review analyzes the current biomarkers used in monitoring pancreas transplant, from the simple and time-tested, to more sophisticated, including markers of allo- and autoimmunity, that are likely to play a larger role in future studies.Evaluation of alloimmunity includes serum levels of donor-specific antibody, and, ultimately, pancreas transplant biopsies with C4d staining. Our center has focused on markers of autoimmunity, including assessment of autoantibodies and autoreactive T cells. We have found that conversion of autoantibodies (including GAD65, IA-2, and ZnT8), or the development of a new positive autoantibody, particularly ZnT8, are associated with type 1 diabetes (T1D) recurrence in the pancreas transplant. Autoreactive T cells have also been identified in the peripheral blood, pancreas transplant and peripancreas transplant-lymph nodes, that have the potential to mediate human β/islet cell destruction in vivo.The monitoring of pancreas transplant biomarkers, particularly those associated with autoimmunity, has led to new insights into the pathogenesis of T1D. Progress in the elucidation of mechanisms of autoimmunity may lead to novel therapeutic approaches to both T1D recurrence of the pancreas transplant and perhaps also new onset T1D.
- Evidence for an important role of both complement-binding and noncomplement-binding donor-specific antibodies in renal transplantation. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):433-40.
The review describes the current clinical relevance of circulating anti-human leukocyte antigen (anti-HLA) antibodies in kidney transplantation and discusses recent improvements in their characterization that provide new insights into the identification and management of important clinical outcomes.Recent studies addressing the relationships between donor-specific anti-HLA antibody (HLA-DSA) properties (i.e., their strength, complement-binding capacity, and IgG subclass composition) and allograft injury and survival have highlighted their relevance in the prediction of antibody-mediated injury and allograft loss.Antibody-mediated rejection is the leading cause of kidney allograft loss. Although considerable experimental and clinical evidence suggests a causal effect of circulating HLA-DSAs in antibody-mediated rejection and allograft failure, HLA-DSAs induce a wide spectrum of injuries to the allograft that illustrate the need to delineate the characteristics of HLA-DSAs that confer pathogenesis. Current risk stratification is based on HLA-DSA characteristics, including antibody specificity, HLA class, and strength. Recently, the complement-binding capacity of HLA-DSAs has been recognized as a clinically relevant marker for predicting pathogenicity and allograft loss. Emerging data also support a role for HLA-DSA IgG subclass composition in discriminating distinct patterns of antibody-mediated injury. This progress in our understanding of HLA-DSA pathogenicity provides new tools to stratify individual immunological risks. However, specific prospective studies addressing immunological risk stratification in large and unselected populations are required to define the clinical benefit and cost-effectiveness of such a comprehensive assessment of HLA-DSAs before implementation in current clinical practice.
- Pancreas transplantation in unconventional recipients. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):393-8.
Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations.An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future.Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.
- Novel immunotherapeutic strategies to target alloantibody-producing B and plasma cells in transplantation. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):419-26.
There is an unmet need for immunotherapeutic agents that target humoral alloimmunity in solid organ transplantation. This includes sensitized patients with preformed donor-specific human leucocyte antigen antibodies and patients who develop de-novo donor-specific antibodies, both of which are associated with acute and chronic antibody-mediated rejection and allograft loss.In this review, we discuss recent progress in the generation of B-cell and plasma cell-targeted therapeutics, with an emphasis on novel agents. To deplete or inhibit B cells, B-cell-specific mAbs have been developed, including CD20, CD22, CD19 and bi-specific antibodies that target two B-cell antigens. In addition, inhibition of B-cell-activating cytokines, such as B cell-activating factor, may also reduce allo-B-cell activation. Plasma cells remain a difficult therapeutic target, but inhibition of germinal centre responses via costimulatory blockade or IL21 neutralization, induction of plasma cell apoptosis using proteasome inhibitors or disruption of the plasma cell niche are potential avenues being explored.The ultimate aim of these animal and human studies is to develop agents that efficiently target humoral effectors, whilst sparing B and plasma cells with a regulatory capacity to promote long-term allograft survival, but we remain some distance away from this goal.
- Long-term outcome after pancreas transplantation: a registry analysis. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):377-85.
Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the most important risk factors for short-term survival of a pancreas transplant, more information about factors that distinguish short-term from long-term graft function is needed.Analysis of 21 328 pancreas transplants from the International Pancreas Transplant Registry, performed from 1984 to 2009 (minimum 5-year follow-up), shows a significant improvement in long-term patient survival and pancreas graft function. Total 5-and 10-year pancreas graft function rates are 73 and 56%, respectively, for simultaneous pancreas-kidney transplants; 64 and 38%, respectively, for pancreas after kidney; and 53 and 36%, respectively, for pancreas transplants alone. The most influential period is the first year posttransplant. Recipients who reach this time point with a functioning graft have a much higher probability for excellent long-term graft function. Important factors influencing long-term function were features that described the quality of the deceased donor. Pancreas transplants in younger, high panel reactive antibody, or African-American recipients also showed an increased risk of early graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants.With careful recipient and donor selection and close follow-up in the first year posttransplant, not only good short-term but also long-term pancreas graft function and, therefore, durable metabolic control can be achieved for the diabetic patient.
- Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):368-74.
Antibody-mediated rejection (AMR) has emerged as a leading cause of allograft loss in solid organ transplantation. A better understanding of AMR immunopathology is a prerequisite to improve its management.The prevalent dogma considers that AMR is the consequence of a thymo-dependent B-cell response against donor-specific polymorphic antigens (mainly mismatched human leukocyte antigen molecules).Nevertheless, antibodies directed against nonpolymorphic antigens expressed by the graft are also generated during chronic rejection and can contribute to allograft destruction. This implies that a breakdown of self-tolerance occurs during chronic rejection. Accumulating evidence suggests that this event occurs inside the ectopic 'tertiary' lymphoid tissue that develops within rejected allografts.Thus, AMR should be viewed as a complex interplay between allo- and autoimmune humoral responses.The interplay between allo- and autoimmune humoral responses in chronic rejection highlights several unmet medical issues like better diagnosis tools are needed to screen recipients for nonhuman leukocyte antigen alloantibodies and autoantibodies, therapeutic strategies shall aim at blocking the response against alloantigens but also the breakdown of self-tolerance that occurs within tertiary lymphoid tissue.
- Current outcomes in islet versus solid organ pancreas transplant for β-cell replacement in type 1 diabetes. [Journal Article]
- Curr Opin Organ Transplant 2016 Aug; 21(4):399-404.
With continued optimization of islet isolation and immunosuppression protocols, the medium-term rates of insulin independence following islet transplantation have improved significantly. This review evaluates the most up-to-date outcomes data for both solid organ pancreas and islet transplantation to develop an algorithm for selection of β-cell replacement in type 1 diabetes patients.Solid organ pancreas and islet transplantation have both displayed improved rates of 5-year insulin independence, largely attributable to improvements in immunosuppressive regimens. The medium-term rates of insulin independence following islet transplantation in highly selected type 1 nonuremic diabetic recipients is beginning to approach the success rates observed following solitary pancreas transplantation.Although pancreas transplantation has historically been favored for β-cell replacement, current outcomes following islet transplantation justify the use of this minimally invasive therapy in carefully selected patients. Pancreas transplant remains the procedure of choice for β-cell replacement in uremic patients. Islet transplantation should be considered in nonuremic patients with low BMI and low insulin requirements, patients lacking the cardiovascular reserve to undergo open abdominal surgery, or patients who elect to forego the risks of a major operation in exchange for an increased risk of islet graft failure.