Erik B. Finger

In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.

When ligand becomes receptor—tolerance via B7 signaling on DCs

CTLA-4–Ig is used to block the costimulation of T cells to interfere with their activation. This reagent may actually be working by provoking DCs to catabolize tryptophan, thereby depriving T cells and contributing to their demise.

Amplification of Autoimmune Response through Induction of Dendritic Cell Maturation in Inflamed Tissues

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed β cell-derived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40high intra-islet DCs up-regulated CCR7, and a small number of CD40high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.

Ten-Year Outcome after Rapid Discontinuation of Prednisone in Adult Primary Kidney Transplantation

BACKGROUND AND OBJECTIVES Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied. RESULTS Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P<0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups. CONCLUSIONS Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

A Composite Risk Model for Predicting Technical Failure in Pancreas Transplantation

Technical failure (TF) continues to have a significant impact on the success of pancreas transplantation. We assessed risk factors for TF in 1115 pancreas transplants performed at a single center between 1998 and 2011. The overall TF rate was 10.2%. In a multivariable model, donor BMI ≥30 (HR 1.87, p = 0.005), donor Cr ≥2.5 (HR 3.16, p = 0.007), donor age >50 (HR 1.73, p = 0.082) and preservation time >20 h (HR 2.17, p < 0.001) were associated with TF. Bladder drainage of exocrine secretions was protective (HR 0.54, p = 0.002). We incorporated these factors in a Composite Risk Model. In this model the presence of one risk factor did not significantly increase risk of TF (HR 1.35, p = 0.346). Two risk factors in combination increased risk greater than threefold (HR 3.65, p < 0.001) and three risk factors increased risk greater than sevenfold (HR 7.66, p = <0.001). The analysis also identified many factors that were not predictive of TF, including previous transplants, immunosuppressive agent selection, and almost all recipient demographic parameters. While the model suggests that two or more risk factors predict TF, strategies to reduce preservation time may mitigate some of this risk.

Evidence That Cd101 Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice

We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a <1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3+ regulatory CD4+ T cells, CD11c+ dendritic cells, and Gr1+ myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D.

Prospective Randomized Trial of Maintenance Immunosuppression With Rapid Discontinuation of Prednisone in Adult Kidney Transplantation

Rapid discontinuation of prednisone (RDP) has minimized steroid‐related complications following kidney transplant (KT). This trial compares long‐term (10‐year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n = 440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n = 151); high‐level tacrolimus (TAC, 8–12 μg/L) and low‐level sirolimus (SIR, 3–7 μg/L) (TACH/SIRL, n = 149) or low‐level TAC (3–7 μg/L) and high‐level SIR (8–12 μg/L) (TACL/SIRH, n = 140). Median follow‐up was ∼7 years. There were no differences between arms in 10‐year actuarial patient, graft and death‐censored graft survival or in allograft function. There were no differences in the 10‐year actuarial rates of biopsy‐proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new‐onset diabetes mellitus were higher with TACH/SIRL (p = 0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p = 0.04). No differences were found in the overall rates of 16 other post‐KT complications. These data indicate that RDP‐based protocol yield acceptable 10‐year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Evolution of Living Donor Nephrectomy at a Single Center: Long-term Outcomes With 4 Different Techniques in Greater Than 4000 Donors Over 50 Years.

Background The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes. Methods All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques. Results We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P < 0.001) and heavier (P < 0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P < 0.001). All 3 LDN modalities required a longer operative time (P < 0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P < 0.001) and reduced the incidence of intraoperative complications (P < 0.001) and hospital length of stay (P < 0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (<30 day, P < 0.001) and long-term (>30 day, P < 0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P < 0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15]). Conclusions In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

Outcomes of pancreas retransplantation.

Background Pancreas retransplantation is associated with increased rates of technical failure and rejection compared to other organ transplants. As such, it is not routinely done, and outcomes are mostly known through registry data. Here we analyze the outcomes of primary versus retransplant for all pancreas transplants done in our program over nearly 35 years. Methods Donor and recipient characteristics and outcomes data were prospectively gathered and recorded in our institutional database. Outcomes of primary and retransplants were reported overall, and then subgrouped by number (second, third, fourth). An in-depth analysis of transplants done after 2003 was included. Rates of technical failure, 1 year acute rejection, graft survival, and patient survival were compared. Results Two thousand one hundred forty-five pancreas transplants were performed at our institution between 1978 and 2012. Four hundred fifteen of these were retransplants. Improvements were seen in technical failure rates and graft survival for both primary and retransplants over time. There were no significant differences in technical failure or patient survival for primary versus retransplants overall, or by transplant number (second, third, fourth). Modern era retransplants had more acute rejection in the first year after transplantation. Retransplants (vs primary) had decreased mid-term death censored graft survival. Transplant type continues to be an important driver of outcome. Conclusions Retransplant outcomes have improved over time, yet increased rejection and immunologic graft loss rates remain associated with pancreas retransplantation. In contrast, risk of technical failure and patient death for primary versus retransplants are similar. Therefore, pancreas retransplantation in highly selected candidates should be considered in experienced centers.

Comparison of Recipient Outcomes Following Transplant From Local Versus Imported Pancreas Donors

The shortage of deceased donor organs for solid organ transplantation continues to be an ongoing dilemma. One approach to increase the number of pancreas transplants is to share organs between procurement regions. To assess for the effects of organ importation, we reviewed the outcomes of 1014 patients undergoing deceased donor pancreas transplant at a single center. We performed univariate and multivariate analyses of the association of donor, recipient and surgical characteristics with patient outcomes. Organ importation had no effect on graft or recipient survival for recipients of solitary pancreas transplants. Similarly, there was no effect on technical failure rate, graft survival or long‐term patient survival for simultaneous kidney–pancreas (SPK) recipients. In contrast, there was a significant and independent increased risk of death in the first year in SPK recipients of imported organs. SPK recipients had longer hospitalizations and increased hospital costs. This increased medical complexity may make these patients more susceptible to short‐term complications resulting from the longer preservation times of import transplants. These findings support the continued use of organ sharing to reduce transplant wait times but highlight the importance of strategies to reduce organ preservation times.