Bruce R. Rosengard

Homeostatic proliferation is a barrier to transplantation tolerance

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.

Consensus Conference Report Maximizing Use of Organs Recovered From the Cadaver Donor: Cardiac Recommendations: March 28–29, 2001, Crystal City, Va

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to ≈6000 to 8000 per year. Because the number of available donor hearts has not increased beyond ≈2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on “Maximizing Use of Organs Recovered From the Cadaver Donor” held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recove...The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on “Maximizing Use of Organs Recovered From the Cadaver Donor” held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described. (Circulation. 2002;106:836-841.)

Report of the Crystal City Meeting to Maximize the Use of Organs Recovered from the Cadaver Donor

A consensus meeting to develop guidelines that would improve the recovery and transplantation of organs from the cadaver donor was held on 28–29 March 2001, in Crystal City, Virginia, sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation. The crisis in organ supply persists and the continuing shortage presents a compelling responsibility for the transplant community to maximize the use of organs procured from cadaver donors.

Aggressive pharmacologic donor management results in more transplanted organs

Background. Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor. Methods. A retrospective analysis of all brain-dead donors recovered in the United States from January 1, 2000, to September 30, 2001, was conducted. HR consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic regression analyses were used to detect differences between the HR group and those donors who did not receive HR. Results. Of 10,292 consecutive brain-dead donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean number of organs from HR donors (3.8) was 22.5% greater than that from nonhormonal resuscitation donors (3.1) (P <0.001). Multivariate analyses showed that HR was associated with the following statistically significant increased probabilities of an organ being transplanted from a donor: kidney 7.3%, heart 4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0%. Extrapolation of these probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to yield a total increase of 2,053 organs. Conclusion. HR stabilizes certain brain-dead donors and is associated with significant increases in organs transplanted per donor.

Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection : an alternative mechanism of allorecognition

Despite evidence that human non-hematopoietic cells, such as vascular endothelium, can activate allogeneic T lymphocytes in vitro, the prevailing view has been that hematopoietic antigen-presenting cells are required to trigger alloimmune responses in vivo. Here we report that mouse non-hematopoietic cells activate alloreactive CD8+ T lymphocytes in vitro and in vivo. We also show that vascularized cardiac allografts are acutely rejected via CD8+ direct allorecognition even if the alloantigen is not presented by hematopoietic professional antigen-presenting cells. Because activation of alloreactive CD8+ T cells by donor-type non-hematopoietic cells can continue for the life of the allograft, these findings present a new clinically relevant mechanism of allorecognition and should be taken into consideration when developing strategies to prevent allograft vasculopathy or to induce tolerance.

Hormonal resuscitation yields more transplanted hearts, with improved early function1

Background. Brain death results in cardiovascular instability and poor organ perfusion in many brain-dead donors. Hormonal resuscitation stabilizes certain brain-dead donors and is associated with significant increases in the numbers of organs transplanted per donor. The goal of this study was to examine the quality of hearts recovered from donors treated with hormonal resuscitation. Methods. A retrospective analysis of 4,543 recipients of hearts recovered from brain-dead donors, reported to the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between November 1, 1999, and December 31, 2001, was conducted. Hormonal resuscitation consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or l-thyroxine. Univariate and multivariate analyses were used to evaluate the quality of hearts from donors who received three-drug hormonal resuscitation (3HR) treatment versus donors who did not receive all three drugs (non-3HR). Death within 30 days and early graft dysfunction were used as endpoints. Results. Hearts from 3HR donors demonstrated a 1-month survival rate of 96.2%, compared with a 92.1% survival rate for non-3HR donor hearts (P <0.01). Early graft dysfunction occurred in 5.6% of 3HR donor hearts and 11.6% of non-3HR donor hearts (P <0.01). Multivariate results demonstrated a 46% reduced odds of death within 30 days and a 48% reduced odds of early graft dysfunction. Steroids alone and steroids plus triiodothyronine/l-thyroxine also significantly reduced prolonged graft dysfunction. Conclusions. This study suggests that 3HR treatment of brain-dead donors results in increased numbers of transplanted hearts, with improved short-term graft function.

Increased transplanted organs from the use of a standardized donor management protocol.

The organ shortage has resulted in increasing recipient waiting lists and waiting‐list deaths. The increased use of expanded donors has been associated with increased discarding of procured organs because of poor organ function. A structured donor management algorithm or critical pathway was tested to determine its effect on the donor management and procurement process. A pilot study examined donors from 88 critical care units in 10 organ procurement organizations managed under the critical pathway and compared them to retrospective data collected at those same pilot sites. The total number of organs both procured and transplanted per 100 donors was significantly greater (p < 0.01) in the critical pathway group when compared to the control group. There was no significant difference in 1‐year graft survival for any of the organs recovered, and no significant difference in the rate of delayed graft function in the kidneys transplanted. Use of a structured donor management algorithm results in significant increases in organs procured and organs transplanted without any reduction in the quality of the organs being transplanted.

Induction of specific tolerance to class I-disparate renal allografts in miniature swine with cyclosporine

Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (i.e., ag→ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (i.e., gg→dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, i.v. q.d. for 12 days. This protocol led to the induction of long-term (>100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7 ± 0.9 days (P<0.0001). The specificity of tolerance was assessed both in vivo

Mechanical Cardiac Support 2000: Current Applications and Future Trial Design

The conference was conducted with financial and other support from the following organizations: American College of Cardiology, American Heart Association, International Society for Heart and Lung Transplantation, American Society of Transplantation, Heart Failure Society of America, American Association for Thoracic Surgery, the Society of Thoracic Surgeons, and the American Society of Transplant Surgeons.* Additionally, participants included members of these agencies: Food and Drug Administration, National Institutes of Health, and the American Society for Artificial Internal Organs. ### TABLE OF CONTENTS Impact Statement 337 Introduction 338 Executive Summary 338 Heart failure presents an increasing public health burden of morbidity and mortality even as the mortality from coronary artery disease and hypertension is decreasing. While effective pharmacologic therapies have improved outcomes for mild-moderate heart failure, the impact of newer therapies and mechanical circulatory support for advanced heart failure has not yet been realized. Implantable devices have been shown to be safe and effective as bridges to cardiac transplantation, but further work is needed to establish the role of mechanical support for myocardial recovery and for long-term support. This conference was held to assess current mechanical support applications and future trial designs for investigation affecting this public health issue. The participants concluded that important differences between devices and drugs may warrant novel study designs characterized by innovation and flexibility. While the randomized clinical trial remains the most powerful tool for unambiguous comparison of interventions, variations may include timed graduation from control to investigational therapies, assignment influenced by patient risk or patient preferences and criteria for an optional crossover to compassionate device use. A major impact would result from a national outcomes database for advanced heart failure that identifies high-risk populations with the greatest potential for benefit from newer therapies and thus facilitates the design of devices and device trials. A separate registry with industry of outcomes after …

Bilateral versus single lung transplantation for chronic obstructive pulmonary disease

OBJECTIVE Traditionally, despite ventilation/perfusion mismatch, single lung transplantation has been the mainstay for end-stage chronic obstructive pulmonary disease. We tested the hypothesis that bilateral sequential lung transplantation has better short- and intermediate-term results than single lung transplantation for chronic obstructive pulmonary disease. METHODS One hundred twenty-six consecutive lung transplants have been performed from November 1991 to March 1996. Seventy-six have been for chronic obstructive pulmonary disease. The diagnosis of this disease includes emphysema (80.3%), alpha 1-antitrypsin deficiency (9.2%), lymphangioleiomyomatosis (7.9%), and obliterative bronchiolitis (2.6%). Twenty-nine transplants have been bilateral and 47 have been single. Mean age was 55.3 for patients having single lung transplantation and 48.8 for those having bilateral lung transplantation (p = 0.001). The distribution of the diagnoses was similar between the two groups. At 6 months, there were 29 survivors of single lung transplantation and 20 survivors of bilateral lung transplantation, with complete data for evaluation. Pulmonary function tests and 6-minute walk tests were evaluated at a mean of 15.4 and 12.8 months after transplantation, respectively. RESULTS Sixty-day mortality was 21.3% for single lung transplantation versus only 3.45% for bilateral lung transplantation (p = 0.03). Additionally, Kaplan-Meier analysis revealed 1- and 2-year survivals of 71.1% and 63.3% for single lung transplantation versus 90% and 90% for bilateral lung transplantation, respectively. Multiple major morbidities were analyzed. Primary graft failure was significantly reduced in the bilateral group (p = 0.049). Both 6-minute walk tests and forced expiratory volume in 1 second were improved from baseline by both single and bilateral lung transplantation (p = 0.001). CONCLUSIONS Bilateral lung transplantation improves forced expiratory volume in 1 second and 6-minute walk tests significantly over single lung transplantation (p < 0.0001). Both perioperative mortality and Kaplan-Meier survival (to 3 years) are significantly improved when bilateral rather than single lung transplantation is used for chronic obstructive pulmonary disease in our series (p < 0.05). This is probably the result of significantly reduced primary graft failure.