Therapeutic manipulation of T cell chemotaxis in transplantation.

T cell migration and trafficking are regulated by the well defined cellular processes of rolling, activation, tight adhesion, arrest and diapedesis. These processes are, in turn, controlled by molecular events involving integrins, selectins, chemokines and chemokine receptors. Recent studies have shown that sphingosine 1-phosphate receptors and their ligands are also important molecular modulators of migration and trafficking. Many of these molecules are appropriate targets for preventing allograft rejection or for achieving tolerance. Studies of migration and trafficking have also shown that the anatomic choreography of alloantigen presentation and T cell encounter with alloantigen and immunosuppression, are over-riding determinants of T cell priming versus tolerization.

Underutilization of pancreas donors.

BACKGROUND: Transplantation of the pancreas has become the treatment of choice for selected patients with type 1 diabetes mellitus. With the current shortage of cadaver donors and the increasing number of diabetic patients on the transplant waiting list, there is a critical need to optimally use all available pancreas grafts for transplantation. We have therefore explored the use of traditionally "less-than-ideal" pancreas donors, including pediatric (4-10 years), older (>or=45 years), obese (weight >or=200 lb), and non-heart-beating donors and donors with an elevated amylase (75% greater than normal values). METHODS: A total of 620 primary simultaneous pancreas-kidney transplantations were performed at our center. We analyzed the ratio of livers to pancreata transplanted at our center and compared this to the United Network for Organ Sharing database. Using univariate and multivariate analyses, we then assessed the impact of these less-than-ideal donors on patient survival, graft survival, and postsurgical complications after simultaneous pancreas-kidney transplantation. RESULTS: A substantial nationwide underutilization of pancreata from donor procurements is demonstrated in the United Network for Organ Sharing database. By using these less-than-ideal donors, the ratio of liver to pancreata procured can be reduced to 1.25:1. Graft survival was not significantly different in patients receiving transplants from obese, non-heart-beating, pediatric, or hyperamylasemic donors compared with grafts from ideal donors. However, grafts from donors 45 years of age or older had significantly lower 1- and 5-year graft survival rates (76% and 65% vs. 90% and 80%, P=0.006). CONCLUSIONS: This study demonstrates that utilization of pancreas grafts from selected, less-than-ideal donors results in good overall outcomes and could potentially expand the organ donor pool.

Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts.

BACKGROUND: Chronic allograft nephropathy (CAN) remains a major barrier to long-term allograft survival. The authors retrospectively compared the development of CAN in recipients of cadaveric (CAD), living-related donor (LRD), and living-unrelated donor (LURD) transplants at their center. METHODS: The authors retrospectively examined the impact of various factors on the incidence of CAN using univariate and multivariate proportional hazards analysis in a single-center kidney transplant population. RESULTS: Between 1 January 1990 and 31 May 2000, 2,140 kidney-alone transplants were performed at the authors' center. The overall 5-year incidence of biopsy-proven CAN was 12.2% (n=203). Risk factors for CAN included the number of transplants (P=0.0001), acute rejection (P=0.0001), panel reactive antibody (P=0.0001), discharge creatinine (P=0.0001), 1-year creatinine (P=0.0015), delayed graft function (P=0.007), total human leukocyte antigen (HLA)-B and -DR mismatches (P=0.0005), recipient age (P=0.003), black donor race (P=0.001), black recipient race (0.0457), donor age (P=0.0053), cold storage time (P=0.019), and cytomegalovirus infections (P=0.002). Interestingly, although the LRD HLA-identical recipients had a significantly lower incidence of CAN (P=0.0015), the incidence of CAN in CAD and HLA-nonidentical LRD recipients did not differ. Graft survival was significantly worse in CAD recipients compared with all other groups (P<0.001). CONCLUSIONS: These results demonstrate the importance of immunologic and nonimmunologic factors on the development of CAN. The disparities in overall graft survival, despite the similarities in CAN rates, suggests that other factors, in addition to CAN, influence the increase in graft loss in CAD transplant recipients.

Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells.

We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4(+)CD25(+)CD62L(high) T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4(+)CD25(+) Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3(+)CD4(+)CD25(+) Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.

Novel immunosuppressants.

Advances in maintenance immunosuppression over the past decade has resulted in dramatic improvements in short- and long-term outcomes in organ transplantation as well as a decreased incidence of acute rejection. However, immunosuppressive drugs need to be given long term, lack specificity, and are accompanied by adverse metabolic derangements, toxicities, the risk of infection and cancer, and a myriad of other side effects. Further, they fail to prevent and control chronic rejection. This review will outline a number of immunosuppressive agents that are currently being explored in experimental and clinical transplantation. These include biologic agents that have more specificity and selectivity, and are aimed at T-cell depletion, blockade of costimulation, adhesion markers, or at novel targets. Most of the studies have been limited to adults but should be applied to the pediatric population as well.

Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis.

Very little is known about the natural history, effects of therapy, and survival after recurrence of hepatocellular carcinoma (HCC) after liver transplantation. All adult patients undergoing liver transplant from September 19, 1988, until September 19, 2002, were reviewed. Only patients with histologically proven HCC in the explant who subsequently developed recurrence were included in further analysis. The endpoints analyzed were survival from time of transplant and survival from time of recurrence. Recipient demographics and laboratory values, technique of transplant (whole cadaver, split, or living donor), and tumor characteristics were analyzed. The time to, location of, and any medical or surgical treatment of recurrences also were considered. Of the 311 patients with HCC in the explant, 57 (18.3%) eventually were diagnosed with recurrent tumor after transplant. Median time to recurrence was 12.3. Five-year survival was significantly lower for patients with recurrence (22%) than for patients without recurrence (64%)(P < 0.0001). Multivariate analysis demonstrated that the size and differentiation of the original tumor, as well as the presence of bone recurrence, were independently associated with survival from transplant in patients with recurrence. When survival from the time of recurrence was analyzed, multivariate analysis showed that the absence of bone metastases, recurrence more than 12 months from transplant, and surgical treatment of the recurrence were independently associated with significantly longer survival. In conclusion, recurrence of HCC significantly shortens survival after transplant. Nonetheless, some patients with recurrence can be expected to live for a considerable period of time. Recurrent disease should be treated surgically when possible, because surgery is independently associated with longer survival.

FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments.

FTY720 stimulates CCR7-driven T cell homing to peripheral lymph nodes (LN) by direct activation of sphingosine 1-phosphate receptors, along with the participation of multidrug transporters, 5-lipoxygenase, and G protein-coupled receptors for chemokines. In this study, we demonstrate that FTY720 also directly stimulates in vitro T cell chemotaxis to CCR2-CCL2, but not to a variety of other chemokines, including CCR5-CCL3/4/5 and CXCR4-CXCL12. FTY720 influences CCR2-CCL2-driven migration through activation of the multidrug transporters, Abcb1 and Abcc1, and through 5-lipoxygenase activity. In vivo administration of FTY720 induces chemokine-dependent migration of T cells in the thymus, peripheral blood, LN, and spleen. The CCR7 and CCR2 chemokine ligands are required for both T cell sequestration in LN and thymic T cell egress following FTY720 administration. Furthermore, FTY720 administration uncovers a requirement for CXCR4 ligands for LN homing, but not for thymic egress, and CCR5 for thymic egress, but not LN homing. FTY720-driven splenic and peripheral blood T cell egress are both independent of CCR2, CCR5, CCR7, or CXCR4. These results indicate that FTY720- and sphingosine 1-phosphate receptor-stimulated T cell migration are dependent on the restricted usage of chemokine receptor-ligand pairs within discrete anatomic compartments.

Medication adherence in pediatric and adolescent liver transplant recipients.

OBJECTIVE: Nonadherence to medications is a leading cause of morbidity in children and adolescents who have had a transplant, yet there are no published data about the use of different methods for detecting whether these children are taking their medications. There are also no published data about the age of transition at which a child assumes responsibility over taking the medications. This information is important if interventions to improve adherence are contemplated. METHODS: We present an analysis of data obtained in the first year of the implementation of an adherence assessment protocol at a pediatric liver transplant clinic in a tertiary medical care center. Data were obtained for children and adolescents who had a liver transplant at least 1 year before the assessments took place. We used 5 adherence detection methods. The 4 subjective methods were self-reported, scaled questionnaires answered by nurses, physicians, caregivers, and patients. For the objective method, a standard deviation (SD) was calculated for tacrolimus blood levels obtained from each patient over time. A higher SD suggests increased variation among patients' blood levels and hence more erratic medication taking. We also asked the patients and caregivers who is responsible for taking the medications and what are the reasons for not taking them. The medical outcome measures were biopsy-proven rejection episodes, number of biopsies regardless of the results, number of hospital admissions, and number of in-patient days. RESULTS: An analysis of 81 cases (258 assessments) revealed that the only method that predicted the medical outcome variables (biopsy-proven rejection and number of biopsies) was the SD of medication blood levels. Patients', clinicians', and caregivers' reports were not predictive. Clinicians' ratings of adherence were not correlated with patients' or caregivers'. The transition of responsibility for medication taking occurred approximately at the age of 12 years. Forgetfulness was cited as the most common reason for nonadherence by patients and caregivers; medication side effects were not frequently cited. CONCLUSIONS: Our results indicate that clinical impression is not sufficient to determine whether children and adolescents are taking their medications after they have had a liver transplant. An objective assessment method should be used. Interventions targeting adherence should address the child's increasing role beginning in early adolescence. A clinical protocol incorporating objective assessments of adherence could potentially be implemented in other settings. It could form the basis for the evaluation of efficacy of interventions seeking to improve adherence to medications.

Donation after cardiac death: the university of wisconsin experience with renal transplantation.

Owing to the shortage of organ donors, there is renewed interest in donation after cardiac death (DCD), formerly referred to as nonheart-beating donation. From January 1984 until August 2000, 382 renal transplants were performed from DCD donors. These were compared with 1089 renal transplants performed from donation after brain death (DBD) donors. The mean warm ischemic time in DCD donors was 16.5 min. There was no statistical difference in cold ischemic time, rate of primary nonfunction, or graft loss in the first 30 days after transplantation. The rate of delayed graft function (DGF) was higher for DCD donors (27.5% vs. 21.3%; p = 0.016) and discharge creatinine was higher in DCD donors (1.92 mg/dL vs. 1.71 mg/dL; p = 0.001). There was no statistical difference in the 5-, 10-, or 15-year allograft survival when DCD donors were compared with DBD donors (64.8%, 44.8%, 27.8% vs. 71.3%, 48.3%, 33.8%; p = 0.054). Likewise, no statistical difference in the rate of technical complications was seen. Our long-term data indicate that the results of renal transplantation from DCD donors are equivalent to long-term allograft survival from DBD donors despite an increase in the rate of DGF. Organ procurement organizations, transplant centers, and hospitals should work to expand the implementation of DCD policies.