Lung transplant candidates who are highly sensitized against human leucocyte antigen present an ongoing challenge with regards to finding immunologically acceptable donors. Desensitization strategies aimed at reducing preformed donor-specific antibodies have a number of limitations. Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes, is a novel agent that has been used to convert positive crossmatches to negative in kidney transplant candidates, allowing transplantation to occur. We present the first case of imlifidase use for antibody depletion in a highly sensitized lung transplant candidate who went on to undergo a successful bilateral lung transplant.

The 2017 Banff meeting provided specific criteria for the diagnosis of tubulointerstitial changes in chronic active T cell-mediated rejection (CATCR), with an emphasis on inflammation in areas of interstitial fibrosis and tubular atrophy, which was thought to reflect an ongoing T cell-mediated alloimmunity. CATCR is considered to occur as a consequence of persistent or recurrent acute T cell-mediated rejection. Acute T cell-mediated rejection is an acute cytotoxic T-cell reaction to HLA antigens on the donor kidneys and causes tubulitis, interstitial inflammation, and intimal arteries. However, unlike early T-cell transplant damage, CATCR can sometimes be difficult to diagnose because the subsequent chronic T-cell damage can become more complex from the accumulation of previous immune and nonimmune injuries. Furthermore, scoring inflammation in areas of interstitial fibrosis and tubular atrophy has potential problems because other diseases and not even native kidneys can have scattered inflammatory cells. Therefore, detailed insights on the pathogenesis of CATCR are indispensable for appropriate diagnosis and further treatment. In this study, the pathologic characteristics and possible factors involved in the interstitial lesions in both typical and complex cases of CATCR are discussed.

Computational mechanistic models constitute powerful tools for summarizing our knowledge in quantitative terms, providing mechanistic understanding, and generating new hypotheses. The present review emphasizes the advantages of reusing publicly available computational models as a way to capitalize on existing knowledge, reduce the number of parameters that need to be adjusted to experimental data, and facilitate hypothesis generation. Finally, it includes a step-by-step example of the reuse and adaptation of an existing model of immune responses to tuberculosis, tumor growth, and blood pathogens, to study donor-specific antibody (DSA) responses. This review aims to illustrate the benefit of leveraging the currently available computational models in immunology to accelerate the study of alloimmune responses, and to encourage modelers to share their models to further advance our understanding of transplant immunology.

This case describes a 34year old female who underwent an HLA identical living donor kidney transplant with a positive flow cytometric crossmatch (FCXM), but without any donor specific antibody (DSA). Tests to detect non-HLA antibody and autoantibody were negative. Allograft functioned well without rejection. She later received a pancreas allograft, again with a weakly positive FCXM, without DSA. After good initial graft function, she developed hyperglycemia six weeks posttransplant. Cross-sectional imaging demonstrated non-enhancing pancreas allograft with new vein thrombosis. She underwent transplant pancreatectomy, the explant pathology demonstrated changes consistent with severe acute antibody mediated rejection (AMR) causing thrombosis of the pancreas allograft. She had also developed several de-novo class-I DSAs at this time. Despite extensive testing, we could not identify a causative antibody for the initial positive FCXMs or its role in the eventual rejection of the pancreas allograft.

Atypical hemolytic uremic syndrome (aHUS) has gained increased visibility over several years as an important cause of renal failure. Unfortunately, diagnosis is often difficult because individual courses can be highly variable depending the causative genetic mutations. Here we present the case of a patient with a failed renal allograft and acute failure of a second allograft who was ultimately diagnosed with aHUS. Interestingly, he developed early de novo donor specific antibodies (DSA) after the second renal transplant in context of likely recurrent aHUS. Terminal complement inhibition with eculizumab resulted in prompt improvement of renal allograft function.

Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared with current standard of care. Current trial design is not leading to novel therapies improving long-term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5- and 10-year graft outcomes, more effective treatment for high immunological risk and sensitized (including donor-specific antibody) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015, the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured to ensure that short- and long-term clinical outcomes continue to improve.

Use of induction therapy after kidney transplant is based on immunologic risk status, but accurate assessment of risk in the era of advanced immunologic testing can be complex. Here, we describe the case of a young kidney recipient who had a Castleman disease, often regarded as a benign lymphoma. Our patient, a white male patient with Castleman disease, underwent a first kidney transplant with rabbit antithymocyte globulin induction but returned to dialysis after primary nonfunction occurred. A second donor became available who shared 3 class I HLA antigens with the first donor, but only low-level isolated donor-specific antibodies toward HLA-Cw were detected (mean fluorescence intensity < 1000). After consideration by clinicians, the patient received a second transplant and was again given rabbit antithymocyte globulin induction (total dose 6 mg/kg). Graft biopsy at month 3 showed no evidence of microvascular inflammation, and the patient was C4d negative. At last follow-up (18 mo), serum creatinine level was 11 mg/dL and Castleman disease remained quiescent. In this challenging case, after weighing various factors concerning immunologic risk status and risk for posttransplant lymphoproliferative disease in the presence of Castleman disease, induction with rabbit antithymocyte globulin appeared to be the appropriate option. Patients with end-stage renal disease and quiescent Castleman disease should receive induction therapy, with close monitoring.

\"Epitope matching\" has become a buzz word in solid organ transplantation. Its goal is to improve matching between donor and recipient, to minimize risk for antibody-mediated rejection and to reduce sensitization associated with graft failure. Current software allows identification and enumeration of amino acid sequence mismatches in the form of HLA eplets; however, \"eplets\" and \"epitopes\" are not interchangeable terms, and the understanding of what contributes to the antigenicity and immunogenicity of HLA B cell epitopes is still very limited and inadequate. In fact, we still do not know what constitutes an HLA epitope or how to define it in a clinically useful way. To allow for judicious implementation of epitope matching, it is critical to explore the full spectrum of factors that affect allorecognition. In exploring antibody-binding patterns, we have uncovered a potential tool-currently hidden in plain sight-that may shed light on some aspects of epitope characteristics.

Antibody-mediated rejection after liver transplant, especially when the donor is not a direct relative; it is associated with additional inconvenience for patients. We encountered a case in which antibody-mediated rejection because of de novo donor specific antibodies against donor human leukocyte antigen developed 6 months after ABO-compatible living-donor liver transplant and was treated with retransplant. A 38-year-old man with hepatitis B virus-related hepatocellular carcinoma underwent living-donor liver transplant with a graft from his wife. Six months later, he experienced fatigue and jaundice. Liver biopsy revealed C4d deposits, and histologic examination showed an antibody-mediated rejection pattern. We re-evaluated recipient-donor human leukocyte antigen matching and tested the patient\'s blood for antihuman leukocyte antigen donor-specific antibodies against donor human leukocyte antigen. De novo auto-antibodies against human leukocyte antigen-DQ6 were identified by Luminex single antigen beads.Because exhausting all treatment options, a rescue second living-donor liver transplant was planned with the patient\'s stepdaughter as the donor. Pretransplant human leukocyte antigen matching was performed, and the patient was discharged without event. Two months later, hyperbilirubinemia was noted, and a residual common bile duct from the first donor with chronic fibrosis and stricture was strongly suspected. Redo hepaticojejunostomy was successfully performed, with no problems during 1-years\' follow-up. Thus, liver retransplant could be a rescue treatment for antibody-mediated rejection complicated with hepatic failure.

Achievement of an immunosuppression-free condition defined as clinical operational tolerance is an ideal goal. We hereby report a case of clinical operational tolerance in a patient whose allograft is functioning normally, without immunosuppression, for more than 3 years. The patient withdrew from immunosuppression in 2011 following which his serum creatinine was 1.34 mg/dl and proteinuria was 178 mg/24 h. Flowcytometric studies showed an elevated number of B lymphocytes and NK cells. IL-10 cytokine levels had increased, whereas those of IFN-γ decreased, suggesting that both B lymphocytes and NK cells, with their immunoregulatory function, contribute to the maintenance of long-term graft function. Consequently, further studies in understanding the interactions of NK cells and B lymphocytes may give us a better insight into the underlying mechanisms that underpin organ tolerance.