Platelet responses to agonists in a cohort of highly characterised platelet donors are consistent over time.

BACKGROUND AND OBJECTIVES: Platelet function shows significant inheritance that is at least partially genetically controlled. There is also evidence that the platelet response is stable over time, but there are few studies that have assessed consistency of platelet function over months and years. We aimed to measure platelet function in platelet donors over time in individuals selected from a cohort of 956 donors whose platelet function had been previously characterised. MATERIALS AND METHODS: Platelet function was assessed by flow cytometry, measuring fibrinogen binding and P-selectin expression after stimulation with either cross-linked collagen-related peptide or adenosine 5'-diphosphate. Eighty-nine donors from the Cambridge Platelet Function Cohort whose platelet responses were initially within the lower or upper decile of reactivity were retested between 4 months and five and a half years later. RESULTS: There was moderate-to-high correlation between the initial and repeat platelet function results for all assays (P ≤ 0·007, r2 0·2961-0·7625); furthermore, the range of results observed in the initial low and high responder groups remained significantly different at the time of the second test (P ≤ 0·0005). CONCLUSION: Platelet function remains consistent over time. This implies that this potential influence on quality of donated platelet concentrates will remain essentially constant for a given donor.

Poor outcomes in hospitalized patients with gastrointestinal bleeding: impact of baseline risk, bleeding severity, and process of care.

OBJECTIVES: Previous studies have found higher mortality rates among inpatients (IPs) compared with new admissions (outpatients, OPs) with acute upper gastrointestinal bleeding (AUGIB), but no studies have investigated the cause for this. The objective of this study was to determine whether the difference in outcomes between IPs and OPs with AUGIB can be explained by differences in baseline characteristics, bleeding severity, or processes of care. METHODS: Data were collected from 6,657 presentations with all-cause AUGIB from 212 UK hospitals as part of a nationwide audit. RESULTS: IPs were older (77 vs. 65 years, P<0.001), had greater comorbidity, and presented with more severe bleeding. There was no difference in median time to endoscopy (24 vs. 24 h, P=0.67) or receipt of endotherapy (19% vs. 17%, P=0.29). IPs had an odds of mortality 4.8 times that of OPs (26% vs. 7%; odds ratio (OR) 4.8, 95% confidence interval (CI) 3.9-5.8); after adjusting for baseline characteristics, this fell by 24% to 3.3 (95% CI 3.2-4.9) and after adjusting for bleeding severity alone to 4.0 (95% CI 3.2-4.9); adjusting for care processes had minimal effect. IPs had more than a twofold increased odds of rebleeding (20% vs. 12%; OR 2.1, 95% CI 1.7-2.5); adjusting for both baseline characteristics and severity of bleeding reduced this by 50% (OR 1.4, 95% CI 1.3-2.4), but process of care had no additional impact. CONCLUSIONS: IPs present with both higher baseline risks and more severe bleeding. These differences in baseline characteristics explain some but not all of the greater mortality of IPs with AUGIB.

National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding.

BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.

Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study.

BACKGROUND AND STUDY AIMS: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. PATIENTS AND METHODS: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. RESULTS: In 4478 patients, earlier endoscopy ( < 12 hours) was not associated with a lower mortality or need for surgery compared with later ( > 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy ( > 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). CONCLUSIONS: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision.

Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions.

OBJECTIVE: To describe patterns of clinical bleeding in neonates with severe thrombocytopenia (ST and platelet count <60 × 10(9) L(-1)), and to investigate the factors related to bleeding. STUDY DESIGN: Seven tertiary-level neonatal units enrolled neonates (n = 169) with ST. Data were collected prospectively on all clinically apparent haemorrhages. Relationships between bleeding, platelet count and baseline characteristics were explored through regression analysis. RESULTS: Bleeding was recorded in most neonates with ST (138/169; 82%), including 123 neonates with minor bleeding and 15 neonates with major bleeding. The most common sites of minor bleeding were from the renal tract (haematuria 40%), endotracheal tube (21%), nasogastric tube (10%) and skin (15%). Gestational age <34 weeks, development of ST within 10 days of birth and necrotizing enterocolitis were the strongest predictors for an increased number of bleeding events. For neonates with ST, a lower platelet count was not a strong predictor of increased bleeding. CONCLUSIONS: The majority of neonates with ST bleed, although most episodes are minor. These findings establish the importance of clinical factors for bleeding risk, rather than minimum platelet count. Further studies should assess the clinical significance of different types of minor bleed for neonatal outcomes, the predictive value of minor bleeding for major bleeding and the role of platelet transfusions in preventing bleeding.

Multimodality imaging of exuberant mitral annular calcification in a patient presenting with transient ischaemic attack.

We report an unusual case of calcification of mitral valve annulus imaged with multiple non-invasive modalities in a patient who suffered a transient ischaemic attack, probably from thrombus overlying the mitral annular calcification. Both this mode of presentation and the imaging features of the annular calcification were relatively unusual, and the images obtained are remarkably clear and diagnostic.

Better actual 10-year renal transplant outcomes of 80% reduced cyclosporine exposure with sirolimus base therapy compared with full cyclosporine exposure without or with concomittant sirolimus treatment.

OBJECTIVE: Retrospective analysis of 10-year outcomes of sirolimus (SRL) plus varying exposure to cyclosporine (CsA) in combination therapy for renal transplantation. METHODS: Univariate, multivariate, and receiver operating characteristic (ROC) analyses of 10-year outcomes of 167 subjects treated with full exposures to CsA/SRL/steroid versus 233 with CsA/no SRL/steroid who were generally enrolled in randomized trials versus 192 patients prescribed 80% reduced CsA exposure adjunctive to SRL baseline therapy with steroid withdrawal (groups 1, 2, and 3, respectively). RESULTS: Groups 1 and 3 showed greater 1-year graft survivals (GS) than group 2 (93% and 94% vs 86%; P=.05, particularly when mean SRL C0≥10.5; P=.02); fewer acute rejection episodes (11% and 19% vs 40%; P<.001) and more frequent success of steroid withdrawal (47% and 66% vs 27%; P<.0001). Group 3 versus 1 displayed a higher mean glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) formula: 56 versus 49 (P=.02) and 53 versus 41 mL/min per 1.73 m2 (P<.001) at 5 and 10 years, respectively. The 10-year GS among group 1 subjects was predicted by a ≥59 mL/min per 1.73 m2 at 1 year using ROC. Multivariate analysis showed factors predictive of 10-year GS among group 1 to include living donor source (P=.004), younger recipient age (P=.02), and fewer HLA-mismatches (P=.02). For group 3, the adverse factors were lower MDRD (P=.01); hypercholesterolemia (P=.01), and advanced donor age (P=.02). Group 3 versus 1 subjects displayed fewer skin tumors (2.6% vs 7.1%; P=.04), sepsis bouts (3.6% vs 9%; P=.04), and herpes virus infection (10% vs. 23%; P=.002), but more urinary tract infections (64% vs 53%; P=.04) and wound problems (43.7% vs 25.1%; P<.0001). CONCLUSION: An 80% reduction of de novo CsA exposure in combination with SRL engendered improved renal function as well as better graft survival at 10 years compared with patients treated with full CsA exposures with or without SRL co-therapy.

Fifty years in the vineyard of transplantation: looking back.

The past 5 decades have documented remarkable advances in basic knowledge and clinical expertise in transplantation. The first 12 years of this half century of my participation in the enterprise were consumed with the isolation, chemical characterization, and application of histocompatibility antigens purified from mouse, guinea pig, and human tissues, demonstrating that their specificity was based on unique amino acid sequences in protein structures. Initial unsuccessful attempts to use native molecules to induce tolerance in rat renal or heart transplantation models were followed by limited success when they were administered with a brief perioperative course of cyclosporine (CsA). Production of allochimeric constructs of class I major histocompatibility complex molecules bearing donor-type amino acid substitutions into the host-type C-terminal portion of the α1 helix yielded tolerogens whose activity was not dependent on conditioning with CsA or total lymphoid irradiation (TLI). The allochimeric molecules serve as altered peptide ligands that induce an aberrant T-cell signal 1 response producing transplantation tolerance. The potent activity of CsA in this experimental model was extended to clinical settings. Pharmacologic tools were employed to explore intra- and interindividual variations in drug exposure leading to the development of a better drug formulation. However, the intrinsic nephrotoxicity of CsA necessitated marked 80% reductions in de novo drug exposure as were achieved by exploiting the synergistic pharmacodynamic and pharmacokinetic interactions of CsA with sirolimus. The final decade in this 50-year experience includes editorship of this journal with marked changes in its direction. These experiences have afforded insights into future avenues for preclinical exploration and therapeutic drug development.

New-onset diabetes after renal transplantation: diagnosis, incidence, risk factors, impact on outcomes, and novel implications.

OBJECTIVE: New-onset diabetes after transplantation (NODAT) is a multifactorial, complex metabolic disorder associated with impaired long-term graft function, reduced recipient survival, and increased risks of cardiovascular disease and infectious complications. The impact of NODAT is generally underestimated partly due to the inconsistent criteria that have been previously used for its diagnosis and to the generally short observation periods. The aim of this article was to review the recent literature on NODAT and to highlight the novel implications. FINDINGS: The 2010 American Diabetes Association guidelines provide useful, simplified criteria to unify the diagnosis including application of hemoglobin A1C levels. We sought to establish the impact of various modifiable and nonmodifiable risk factors. A vast number of papers have examined the effects of immunosuppressive medications on the development of NODAT: Neither calcineurin inhibitor nor sirolimus (SRL) or steroids seems to be innocent of contributing to it. Immunosuppressants account for 74% of the occurrence of NODAT. Among modifiable risk factors, obesity is independent and significant, with great prevalence in the population. In additional to lifestyle modifications, the role of bariatric surgery (BS) either before or after transplantation is highlighted herein as a strategy to reduce disease in the view of the results among overweight, nontransplanted patients. SUMMARY: Because of the strong association between high glucose values in the early posttransplant period and the development of NODAT, the condition must be recognized early after (or even before) transplantation by intensive screening. Patients at risk for NODAT must modify appropriate risk factors and particularly undergo pretransplant planning and/or posttransplant adjustment individualizing immunosuppressive therapy to mitigate the risk of this serious complication.

Sirolimus therapy predisposes to new-onset diabetes mellitus after renal transplantation: a long-term analysis of various treatment regimens.

PURPOSE: This retrospective analysis evaluated the impacts of sirolimus (SRL), cyclosporine (CsA), and steroids (S) on the occurrence, treatment, and complications of new-onset diabetes after transplantation (NODAT). METHODS: We compared 4 groups: group 1, SRL plus full-exposure CsA/S (n = 118); group 2, full-exposure CsA/S/no SRL ± antiproliferative drug (n = 141); group 3, SRL plus reduced CsA exposure/S (n = 212); and group 4, no SRL/full-exposure CsA/S ± antiproliferative drug (n = 43). RESULTS: NODAT rates reflected the level of CsA exposure; at 10 years 54% versus 30% for groups 1 versus 2 (P = .0001); at 5 years 30% versus 21% for Groups 3 versus 4 (P = .3); 81% of cases were detected within 1 year. The lower NODAT rate in group 3 reflected a benefit of reduced CsA exposure (P = .02; hazard ratio (HR), 1.006). Group 1 showed higher CsA (P = .0001) and lower SRL concentrations (P = .016) versus group 3. CsA exposure closely correlating with NODAT among group 1 (P = .0001) was the major difference between groups 1 and 3 (P = .04; HR, 0.97). Differences in steroid treatment did not play a significant role in NODAT. Comparing groups 1 and 2, SRL was an independent risk factor for NODAT (P = .004; HR, 3.5). CONCLUSIONS: Our 10-year experience revealed SRL to be an etiologic agent for NODAT, displaying interactive, possibly pharmacokinetic, and pharmacodynamic effects with concomitant CsA in combination treatment.

Mortality from acute upper gastrointestinal bleeding in the United kingdom: does it display a "weekend effect"?

OBJECTIVES: An increased mortality in patients presenting to hospital at weekends has been observed for several medical conditions. The aim of this study is to examine the relationship between weekend presentation to hospital following acute upper gastrointestinal bleeding and mortality. METHODS: Data were collected on 6,749 patients presenting to 212 UK hospitals. A logistic regression model was used to examine the relationship between weekend presentation to hospital and mortality. RESULTS: Patients presenting at the weekend were more likely to present with shock (39% vs. 36%), hematemesis (41% vs. 38%), and receive red cell transfusion (42% vs. 39%). Only 38% of those presenting at weekends underwent endoscopy within 24 h compared with 55% admitted on weekdays (adjusted odds ratio (OR)=0.47, 95% confidence interval (CI)=0.41-0.54), although the proportion of all patients receiving endoscopic therapy was identical at weekends compared with weekdays (24%). After adjustment for confounders, there was no evidence of a difference between weekend and weekday mortality (OR=0.93; 95% CI=0.75-1.16). Similar results were seen when restricting the analysis to those patients who underwent endoscopy (n=5,004) (OR=0.87, 95% CI=0.65-1.16). There was no difference in the OR for mortality for weekend compared with weekday presentation between patients presenting to hospitals with an out-of-hours (OOH) endoscopy rota compared with those presenting to hospitals without such a facility. CONCLUSIONS: In this large prospective study of acute upper gastrointestinal bleeding in the United Kingdom, there was no increase in mortality for weekend vs. weekday presentation despite patients being more critically ill and having greater delays to endoscopy at weekends. Provision of an OOH endoscopy service at weekends in the remaining UK hospitals may not lead to further reductions in case fatality, although a reduction in OOH endoscopy provision from current levels could lead to an increase in mortality at weekends.

Frontiers in immunosuppression.

Because of the pleiotropic toxicities of available immunosuppressants, new approaches have employed agents that seek to mitigate nephrotoxicity. Phase III trials of belatacept, a conjugate of cytotoxic lymphocyte antigen-4 (CTLA-4) and immunoglobulin that seeks to block T-cell activation signal 2, displayed significantly improved renal allograft function among standard (but much less so, among extended) criteria donor kidneys. However, there was no evident protection against chronic processes. Indeed, the study arm experienced an increased incidence of acute rejection episodes and posttransplant lymphoproliferative diseases. A Phase II trial of sotrastaurin, a nonselective protein kinase C (PKC) inhibitor that may exert effects on signals 1 and 2, showed little benefit on renal graft function with an excess of acute rejection episodes, tachycardia, and serious infections when used as base therapy in combination with mycophenolate sodium and steroids after withdrawal of tacrolimus (TRL) treatment at 3 months. Phase II trials of tasocitimib, a putative blocker of Janus kinase (Jak)3-mediated transduction of signal 3, produced improved renal allograft function compared with TRL-based therapy. However, treated patients showed prominent inhibition of Jak 2, a widely distributed mediator of growth and differentiation signals in a variety of tissues, thereby engendering increased rates of infections and serious diseases. Major advances in this enterprise might be achieved with the discovery of agents that more specifically target intermediates selective for lymphoid cells: For example, lymphocyte cell kinase (lck; signal 1), CTLA-4 itself (signal 2), or Jak 3 (signal 3). Preliminary work in animal models supports these avenues for future drug development.

Addition of induction therapy offsets the hazard of marked calcineurin minimization among renal transplant recipients treated with sirolimus.

AIMS: We sought to examine the improvement in renal function with preserved immunosuppression consequent to reducing de novo cyclosporine (CsA) doses combined with sirolimus and induction antibody treatment. MATERIALS AND METHODS: 408 renal recipients treated de novo with CsA-sirolimus included 91 patients who received high (> 5); 125, medium (2.5-5.0); or 192, low CsA doses (< 2.5 mg/kg/day) together with induction antibody among 5, 48 and 68% of subjects, respectively. At 2 years we excluded 21 (23), 30 (24) and 49 (25%) subjects who experienced the composite end-point, yielding 70 (71), 95 (76) and 143 (74%) cases, whose mean de novo CsA C2 values were 725, 400 and 306 ng/ml; for all cohorts, sirolimus C0 = 10-15 de novo and 8-12 ng/ml during maintenance treatment. The primary end-point--mean 4-year GFR by aMDRD--ascribed "0" to patients who experienced death or graft loss after 2 years. RESULTS: Although low-dose subjects were older (p = 0.008) and heavier (p < 0.001) with grafts exposed to longer cold ischemia times (p < 0.001), they displayed greater GFR: 64.8 versus 48.4 among the high and 54.1 ml/min/1.73 m(2) in the medium dose arms (p = 0.002). Polychotomous logistic regression revealed significant GFR predictors to be CsA dose (p = 0.015) and younger donor age (p < 0.001). Between 2 and 4 years, the incidences of the composite end-point were 17, 14 and 16%; including 13, 10 and 11% rejections. CONCLUSION: 80% reduction in de novo CsA exposure with antibody induction improved renal function at 4 years compared with 50 or 66% reductions.

Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case report.

Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.

Current approaches to the use of sirolimus in renal transplantation.

Sirolimus, a macrolide with immunosuppressive properties, was introduced into clinical practice a decade ago. The optimal use of this drug remains controversial: It displays a wide range of organ and tissue toxicities owing to the critical role of its therapeutic site- the kinase mammalian target of rapamycin-in the signal transduction pathways of numerous cytokines, growth factors, hormones, and nutrients. However, it displays unique, recognized benefits for renal transplant recipients: synergistic interactions with cyclosporine and possibly tacrolimus, allowing marked reduction in exposure to the calcineurin inhibitor; reduction in the frequency of posttransplant malignancies, particularly lymphomas, Kaposi sarcomas, and hypernephromas; and modest nephrotoxicity in comparison with calcineurin inhibitors. Because of its inhibitory effects on endothelial and smooth muscle cell proliferation, sirolimus may be a useful tool to dampen chronic vasculo-obliterative processes that attenuate graft survival. With increasing experience with the drug, the true potential of sirolimus will be realized to be a critical element in the immunosuppressive matrix.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

Living donor kidney transplantation without transmission of multiple sclerosis after 10 years.

We report the case of a successful renal transplant for over 10 years from a living donor with a history of multiple sclerosis.

The ruby anniversary: forty years of publication of Transplantation Proceedings - the first decade: the flowering of immunology and immunogenetics.

The fortieth-ruby-anniversary of publication of Transplantation Proceedings chronicles the major developments in this field of expanding scientific and clinical importance. The first decade of publication included seminal findings in immunogenetics of the major histocompatibility complex-HLA-A, -B, -C, and -D-and immunology of induction and expression of alloimmunity from single cell to mammalian organisms. Initial dissections of destructive versus acceptance mechanisms toward allografts revealed cytotoxic versus suppressive/enhancing cell-mediates and humoral vectors. Initial clinical successes revealed technical accomplishments that warranted broader application of this technology as described in the second decade of the Proceedings-the advent of cyclosporine.