Results of vascularized joint allograft under immunosuppression with cyclosporine

The effects of cyclosporine (CsA), a strong immunosuppressive drug, on vascularized allogeneic joint transplantations were examined. An orthotopical transplant model of a vascularized knee joint allograft was developed using inbred DA and Lewis rats to investigate the fate of grafts following withdrawal of short-term immunosuppression compared to continuous immunosuppression with CsA. Five isograft controls acquired solid bone union at both femur and tibia sites within 4 weeks, and joint function as skeletal support was maintained until 25 weeks. Without immunosuppression, ten allografts were severely rejected within the first week, and joint destruction occurred immediately. Twenty-five short-term immunosuppressed rats acquired solid union, but, after withdrawal of immunosuppression, grafted joints showed gradual rejection and were destroyed due to pathological fractures or joint instability, although partial revascularization from the recipient occurred. Ten allografts under continuous immunosuppression at a dose of 10 mg/kg/day showed no rejection and remained viable for 12 weeks postoperatively, but thereafter all rats died. Death was considered to be a side effect of CsA. Fifteen animals, under continuous immunosuppression at a dose of 5 mg/kg/day, showed no rejection except in the bone marrow; the grafted joint function was not effected until 25 weeks. Continuous treatment with low and nontoxic doses (5 mg/kg/day) of CsA was necessary to maintain the functions of the grafted joint. © 1993 Wiley-Liss Inc.     

Histological characteristics of acute rejection in vascularized allografts of bone

Using a genetically defined rat model for the heterotopic transplantation of a vascularized knee in the rat, histological and histochemical studies of acute rejection in vascularized allografts of bone were carried out. The graft consisted of the knee joint with the distal end of the femur, the proximal part of the tibia, the cartilaginous growth plates, the articular cartilage, and a minimum cuff of muscle, which was transferred to a location under the abdominal skin. A total of 160 transplants, including vascularized and non-vascularized isografts, vascularized and non-vascularized allografts that were transplanted across a strong histocompatibility barrier, and vascularized allografts of bone that were transplanted across a weak histocompatibility barrier, were studied by light microscopy at intervals for as long as twelve weeks after transplantation. Vascularized allografts of bone that were transplanted across a strong histocompatibility barrier showed evidence of rapid rejection, similar to that after transplantation of allografts of visceral organs. This was manifested at one week by necrosis of osteocytes, cessation of microcirculatory flow, massive extravasation of red cells, and deposition of fibrin in the marrow. The large vessels demonstrated changes that were characteristic of vascular rejection. Allografts that were transplanted across a weak histocompatibility barrier showed a more gradual, less intense process of rejection that allowed observation of the evolution of the process. In these grafts, the osteoblasts and marrow in the primary spongiosa of the metaphysis were early targets of rejection, as indicated by necrosis of osteoblasts, extravasation of red blood cells, and deposition of fibrin in the marrow spaces. Loss of osteoblasts from the surfaces of osteoid as well as from bone on spicules of calcified cartilage resulted in the cessation of new-bone formation. Calcification of the longitudinal septa between the lowermost hypertrophic chondrocytes was decreased. However, the proliferation and maturation of chondrocytes in the zone of proliferating chondrocytes and in the upper hypertrophic zone continued and resulted in the formation of a thickened growth plate. The loss of osteocytes in other areas of the graft occurred later and only in the areas where the microcirculation had been lost. These data suggest that ischemic damage, which is probably secondary to an immune-related vascular compromise, is a significant factor in the failure of grafts. In the grafts that were transplanted across a weak histocompatibility barrier, the growth of new bone and revascularization by the host occurred by twelve weeks.     

Experimental studies on vascularized allogeneic joint transplantation in rats]

Examination was made on the effects of Cyclosporine A, an immunosuppressive drug, on vascularized joint allografts. Genetically inbred DA and Lewis rats were used and a model of knee joint orthotopical transplantation across the major histocompatibility barrier was developed. Nine non-immunosuppressive allografts failed to acquire bony union. Twenty-seven short term immunosuppressive rats acquired solid union, but following withdrawal of immunosuppression, the grafts were soon rejected and joint function was lost due to pathological fractures of the grafted bone or joint instability. Thirteen allografts of continuous immunosuppression at a dose of 5 mg/kg/day showed no rejection, though the bone marrow did, and there was no impairment of function. The continuous administration of low and non-toxic dose of Cyclosporine A was necessary for maintaining grafted joint functions.     

Influence of SDZ RAD vs. MMF on gastric emptying in renal transplant recipients

SDZ RAD and mycophenolate mofetil (MMF) are increasingly used in the prevention of renal allograft rejection. SDZ RAD, having a macrolide structure, and MMF, known with gastrointestinal side-effects, may have gastric motility modifying properties. Gastric emptying was examined 1 yr after renal transplantation in eight patients taking corticosteroids (CS), cyclosporin A (CsA) and SDZ RAD and six patients treated with CS, CsA and MMF. Comparing the two groups, no significant differences in gastric emptying of solids and liquids were noted. Compared with normal volunteers, solid gastric emptying was faster in the SDZ RAD group and similar in the MMF group. It is concluded that in stable renal transplant recipients treated with MMF, gastric emptying was normal. Because of the impact on drug absorption and gastrointestinal symptoms, further studies are indicated to corroborate the potential prokinetic properties of SDZ RAD.     

The effect of immunosuppression on vascularised allografts. A preliminary report

Five vascularised allografts of the knee joint were performed in dogs immunosuppressed with cyclosporin A and azathioprine. Three survived with normal function for 3 to 4 months after operation. One of the unsuccessful grafts had a failed vascular anastomosis, the other an inadequate blood level of cyclosporin A. All three successful grafts healed well. In two, bone scans, radiographs and biopsies were indistinguishable from successful autografts; in the third the blood supply to the graft failed despite patent anastomoses but the graft healed well with good function. All three grafts were rejected within 2 to 3 weeks of withdrawal of cyclosporin A and azathioprine. In non-immunosuppressed dogs, allografts of the knee, both vascularised and non-vascularised, were rejected within a few days of operation. In two non-vascularised allografts, administration of cyclosporin and azathioprine had no apparent effect on the rate of rejection of the graft.     

Experimental vascularized bone allografting

Presented here is a compendium of studies investigating the fate of vascularized bone allografts. The first set of experiments employ the posterior rib graft in two canine models. The rib-to-mandible model was used to evaluate the rejection phenomena of vascularized bone allografts in an outbred dog model. This ascertained the time course of rejection and histological characteristics of the grafts. Immunosuppression of the graft recipients was attempted with azathioprine and cyclosporine. The results demonstrated that azathioprine was not an effective immunosuppressant, whereas cyclosporine resulted in survival of cortical osteons. The use of the vascularized rib allograft, with and without azathioprine, to bridge the defect in the dog femur was met with failure. Further studies employed a genetically defined rat model to determine the effect of different histocompatibilities on the survival of vascularized knee allografts. Grafts were transplanted from Lewis rats to syngeneic Lewis rats as isografts and to Fischer-344 rats (F-344) and Brown-Norway rats (BN) as allografts. Grafts across a major histocompatibility barrier to BN were rejected by 7 days, whereas grafts across a weak histocompatibility barrier to F-344 were rejected more slowly. The use of cyclosporine in this model abrogated the rejection response when administered to both groups continuously. However, a short course of cyclosporine was effective in preventing rejection in the F-344 animals. Efforts to induce tolerance by blood transfusions, from the donor strain or from a third-party donor, were not effective in preventing rejection.     

Vascularized whole knee joint allografts in rabbits immunosuppressed with cyclosporin A

To develop the surgical model, whole knee joints including the distal femur, proximal tibia, and joint capsule, were raised on a vascular pedicle and then replanted at the same site. Rigid fixation of the bones was achieved using two mini-plates on the tibia and femur. Revascularization of the knee was accomplished by end-to-end anastomosis of the popliteal vessels using standard microvascular techniques, and the vascular and neural supplies to the lower leg and foot were preserved. A total of 21 vascularized whole knee allografts were then similarly performed on a microvascular pedicle between two incompatible strains of rabbit. In a control group of six adult animals, no immunosuppression was administered. Two of these joints were harvested at 1 week and had patent popliteal arteries. The remaining four joints were harvested at 2-3 weeks when they were deteriorating and were found to have occluded popliteal vessels by arteriography. Eight adult allograft recipients were immunosuppressed with cyclosporin A (CyA) at 15 mg/kg per day. One allograft failed at 10 days due to femoral fracture. None of the remaining seven were rejected acutely, and three of them had patent vessels by arteriography and live bone and cartilage by light microscopy when harvested 100 days after transplantation. In another group, seven knee joints were allografted into immature rabbits immunosuppressed with CyA. Again, none rejected acutely, and 90 days later two of the seven allografts had patent vessels by arteriography, growth by serial radiographs, and live bone and cartilage by histological examination. This pilot study suggests that CyA will be useful as an immunosuppressive agent in the study of vascularized bone and cartilage transplantation, and that experimental epiphyseal plate allografting is possible in rabbits.     

Renal allograft tolerance in DLA-identical and haploidentical dogs after nonmyeloablative conditioning and transient immunosuppression with cyclosporine and mycophenolate mofetil

BACKGROUND: Canine models of bone marrow and renal transplantation have provided important preclinical data relevant to developing novel therapeutic protocols for hematopoietic and solid organ transplantation in human beings. Nonmyeloablative transplantation has been shown to induce stable mixed hematopoietic chimerism in normal dogs and correct the phenotype of canine pyruvate kinase deficiency and Glanzman's thrombasthenia. In this study, we investigated the potential for inducing renal allograft tolerance using a nonmyeloablative bone marrow transplantation strategy that induces mixed chimerism in DLA-identical dogs. METHODS: Reciprocal renal allografts were performed in 4 DLA-identical and 4 DLA-haploidentical dogs with nonmyeloablative conditioning (200 cGy total body irradiation [TBI]) and transient immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) with and without simultaneous bone marrow transplantation. Two DLA-identical control dogs received reciprocal renal allografts without TBI or immunosuppression with CSP and MMF. Serum creatinine (Cr) concentration was monitored to assess renal allograft function. RESULTS: The renal allografts were acutely rejected in the 2 DLA-identical dogs without TBI or immunosuppression. There was long-term (>1 year) renal allograft survival as evidenced by a normal (<2.0 mg/dL) serum Cr concentration in both the DLA-identical and DLA-haploidentical dogs that underwent 200 cGy TBI and transient immunosuppression with CSP and MMF either with or without simultaneous bone marrow transplantation. CONCLUSIONS: Nonmyeloablative conditioning (200 cGy TBI) and transient immunosuppression with CSP and MMF induce renal allograft tolerance in DLA-identical and DLA-haploidentical dogs without donor/host mixed hematopoietic chimerism. These findings suggest it may be possible to induce tolerance to solid organ transplants without the need for chronic immunosuppressive therapy or stable hematopoietic chimerism in the setting of both DLA-matched and haploidentical transplants.     

Clinical experience in allogeneic vascularized bone and joint allografting

The allotransplantation of vascularized femoral diaphyses and total knee joints is a novel approach in orthopedic surgery. Allogeneic femoral diaphyses were transplanted into three patients suffering from chondrosarcoma or posttraumatic defects. Total knee joints allografts were transplanted in five patients with large bone defects of the knee and loss of the extensor apparatus caused either by major trauma alone or infection after a major trauma. Bone segments and total joints were harvested from multi-organ donors, perfused with UW-solution and transplanted within cold ischemia times of 18-25 h. Patients were immunosuppressed postoperatively primarily with cyclosporine (Cyclosporin A) and azathioprine. Two allografts (1 femur, 1 knee) were lost due to infections. Seven of the eight patients are able to walk with full weight-bearing posttransplant. Two of the patients with transplanted joint allografts subsequently received total knee arthroplasty implantations. Vascularized bone and joint allotransplantation may serve as a last line of defense treatment before considering lower limb amputation.     

Oral efficacy of the macrolide immunosuppressant SDZ RAD and of cyclosporine microemulsion in cynomolgus monkey kidney allotransplantation

BACKGROUND: 40-O-(2-Hydroxyethyl)-rapamycin (SDZ RAD) is a novel, potent, macrolide immunosuppressant. Its efficacy in rodent transplantation models provided the rationale for us to evaluate the compound in a more relevant, large animal transplantation model. METHODS: Life-supporting kidney allotransplantation was performed in cynomolgus monkeys: rejection was inferred from a rise in serum creatinine or urea and was subsequently confirmed by histopathology. This model was validated with the microemulsion formulation of cyclosporine (i.e., Neoral). Two studies with a microemulsion formulation of SDZ RAD were performed. First, in a dose-finding study, the SDZ RAD dose was reduced in a stepwise fashion until rejection occurred, either with SDZ RAD as monotherapy, or in combination with a fixed, suboptimal dose of cyclosporine. Second, an efficacy study was performed in which two fixed SDZ RAD doses (0.75 and 1.50 mg/kg/ day) were evaluated in monotherapy and compared with the same doses of rapamycin (sirolimus). All immunosuppressants were administered once daily by gastric gavage. RESULTS: Untreated control animals rejected their grafts between 4 and 8 days after transplantation. Cyclosporine (initially at 150 mg/kg/day, reduced to 100 mg/kg/day 2 weeks after transplantation) yielded long-term (>100 days) rejection-free allograft survival in four of five animals. A 10 mg/kg/day dose of cyclosporine led to rejection between 10 and 27 days after transplantation and was considered suboptimal. In the dose-finding study with SDZ RAD monotherapy, rejection occurred in most of the cases (four of six animals) when a dose level of 0.63 mg/kg/day had been reached. Combined with suboptimal cyclosporine, this threshold SDZ RAD dose was about 2-fold lower. In the efficacy study, median graft survival with histologically proven rejection was 32 days (range 8-91 days, n=6) for 0.75 mg(kg/day SDZ RAD and 59 days (range 28-85 days, n=6) for 1.50 mg/kg/day SDZ RAD. For sirolimus, median graft survival was 43 days (range 5-103 days, n=7) for the 0.75 mg/kg/day dose and 56 days (range 8-103 days, n=8) for the 1.50 mg/kg/day dose. There was no statistically significant difference in efficacy between SDZ RAD and sirolimus. CONCLUSION: SDZ RAD, in the absence of any other immunosuppressant and at doses that do not show any overt toxicity, considerably prolongs rejection-free survival of cynomolgus monkeys after life-supporting kidney allotransplantation.     

Fresh allograft of intact growth plate into immature articular cartilage defects in rats]

In three inbred rat strains with a distinct major histocompatibility complex (MHC), MHC-matched allografts (Fisher, RT1l to Lewis, RT1l, n = 39) or MHC-mismatched allografts (Brown Norway, RT1n to Lewis, RT1l, n = 38) of fresh intact cartilage obtained from the tibial epiphyseal growth-plate were grafted into the defects in the femoral articular surface of immature rats. In the controls (n = 72), similar defect on the joint cartilage were made with no epiphyseal plate grafts. The present histological observation was continued throughout one year after transplantation. Total success rate of the repair was significantly better in MHC-matched allografts (92%) than in MHC-mismatched allografts (61%, p less than 0.001) or controls (19%, p less than 0.001). The MHC-matched allografts showed no signs of tissue rejection. However, the MHC-mismatched allografts showed evidence of lymphocyte infiltration and 13 (81%) of 16 grafts were rejected from 12 to 48 weeks after operation. These findings indicate that MHC-matched allografts of intact growth-plate have a potential to repair defects in immature articular cartilage over a long period of time, but MHC-mismatched allografts will eventually be rejected.     

The mechanism of heart failure caused by cardiac allograft rejection

Rejection of the cardiac allograft is often associated with reversible myocardial failure, the mechanism of which is not understood. We have examined this phenomenon in a small animal model that provides the opportunity for multimodality study of the rejection process. Heterotopic cardiac transplantation was performed in the Lewis rat with Lewis X Brown-Norway (allografts) or Lewis (isografts) donors. Without immunosuppression, allografts are completely rejected in 6 to 8 days. At 3 days cardiac grafts were explanted and mounted on a modified Langendorff apparatus for functional measurements or submitted for pathologic examination and biochemical determination of high-energy phosphates. Three-day isografts (n = 9) had minimal histologic changes. Pathologic examination of 3-day allografts (n = 13) showed lymphocytic infiltrate and myocyte necrosis, histologic features for which antirejection treatment is usually given clinically. For grafts subjected to functional studies (n = 11), heart rate, cardiac output, coronary flow, and stroke work were determined at baseline and in response to isoproterenol (3 x 10(-8) mol/ml). Three-day allografts (n = 6) and isografts (n = 5) had similar baseline function. The chronotropic response to isoproterenol was similar in allografts and isografts, but allografts had diminished cardiac output and stroke work after isoproterenol. Adenosine triphosphate levels were normal (41.9 nmol/mg) in 3-day allografts (n = 4). We have evaluated functional, biochemical, and pathologic changes associated with myocardial dysfunction during heterotopic cardiac transplant rejection in a small animal. This model reproducibly demonstrates diminished contractile reserve in 3-day allografts with normal baseline function and high-energy stores but histologically significant rejection.     

Effects of and predictors for tacrolimus rescue therapy among renal transplant patients under cyclosporine-based immunosuppression

BACKGROUND: Though cyclosporine has dramatically decreased rejection rates and improved graft survival rates of renal allografts, there is still a remarkable rate of acute rejection and progressive deterioration of renal function after transplantation. Rescue therapy with tacrolimus has been used for allografts failing under cyclosporine-based treatment in order to get some renal functional recovery or stabilization. The aim was to evaluate tacrolimus rescue therapy for failing allografts under cyclosporine-based immunosuppression for possible prediction factors for success. PATIENTS AND METHODS: Thirty-five renal allograft recipients with failing transplants under cyclosporine-based immunosuppression were enrolled into this study. Renal function was evaluated by reciprocal serum creatinine level (1/Cr) and calculated CCr. The slope of changes in 1/Cr and CCr were calculated before and after tacrolimus therapy. The possible risk factors that affect the outcome of tacrolimus rescue therapy were analyzed. RESULTS: Nineteen patients showed improved renal function (group 1) and 16 patients, persistent deterioration (group 2) after rescue therapy. Group 1 showed positive slopes of changes of 1/Cr and CCr after rescue therapy. Group 2 patients showed persistent negative slopes although less negative than before rescue therapy. Only the posttransplant time was the significant predictive factor for successful tacrolimus therapy (P = .018). CONCLUSION: Tacrolimus rescue therapy improved or stabilized renal function in some patients with failing grafts under cyclosporine-based immunosuppression. To assure a successful rescue effect, it should be given early after transplantation, if there is a tendency toward deterioration of renal function.     

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases

BACKGROUND: The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS: Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS: Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS: We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.     

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.     

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS ≥ 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.     

Immunosuppression with Belatacept‐Based,Corticosteroid‐Avoiding Regimens in De Novo Kidney Transplant Recipients

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.     

Tolerance induction permits the development of graft-versus-host disease: donor-mediated attack following small bowel transplantation in mixed chimeras.

The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibility barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chimeras (ALC), Lewis/ACI F1 (LACF1), and Lewis (LEW) rats all received heterotopic ACI vascularized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GVHD. Preirradiating the donor bowel prior to SBTx can prevent GVHD.     

Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial

BACKGROUND: Living-donor kidney transplant recipients generally do not receive antibody induction. Induction avoidance may not be appropriate, particularly for living-unrelated renal transplant (LURT) recipients, in whom matching may not be optimal. We compared the incidence of acute rejection and graft outcome of LURT recipients who were administered no induction and cadaveric renal transplant (CRT) recipients who were administered anti-CD25 antibody. These groups both had immediate graft function and similar maintenance immunosuppression. METHODS: This retrospective analysis included patients who received kidney transplants between 1999 and 2000. CRT recipients received basiliximab, corticosteroids, mycophenolate mofetil (MMF), and delayed tacrolimus (serum creatinine <3 mg/dL). LURT recipients received tacrolimus (initiated pretransplantation), MMF, and corticosteroids. RESULTS: The analysis included 136 LURT recipients and 126 CRT recipients. CRT recipients included more African Americans (52.4% vs. 30.9%, P<0.01). LURT recipients included more patients with at least one human leukocyte antigen mismatch (97.8% vs. 85.7%, P<0.01). A higher acute rejection rate was observed in LURT recipients at both 6 months (LURT recipients 19.1% vs. CRT recipients 3.2%, P<0.01) and 1 year (21.3% vs. 4.0%, P<0.0004); a higher rate also was observed in African American LURT recipients compared with African American CRT recipients (35.7% vs. 4.5%, P<0.0015) at 1 year. LURT recipients demonstrated a threefold greater rejection risk than CRT recipients who were administered basiliximab (relative risk: 3.6, P<0.002). Graft survival was similar at 1 year. CONCLUSION: The higher rejection rates in LURT recipients (no induction) compared with CRT recipients (basiliximab induction), despite similar chronic immunosuppression (tacrolimus, MMF, and steroids) and immediate graft function, indicate the potential advantage of anti-CD25 induction in LURT protocols to reduce the risk of acute rejection.     

Role of PECAM-1 in acute rejection of fully major histocompatibility complex class II-mismatched cardiac allografts in mice

The aim of this study was to determine the role of platelet-endothelial cell adhesion molecule (PECAM) in acute rejection of vascularized whole organ allografts in vivo. Hearts were transplanted between BALB/c, PECAM-1(-/-), or C57BL/6 wild-type mice. Grafts were harvested on the day of rejection or after 120 days and were analyzed histologically. BALB/c allografts survived significantly longer in PECAM-1(-/-) recipients compared to wild-type controls (8.3+/-0.4 vs. 6.4+/-0.8 days; P<0.05). Survival of PECAM-1(-/-) allografts in BALB/c recipients did not differ from that of wild-type-derived transplants (12.2+/-3.0 vs. 9.3+/-0.7; P>0.05). In all allografts, histology showed massive monomorphonuclear leukocyte infiltration, indicating parenchymal rejection. Immunohistochemistry confirmed in all transplants a preserved donor endothelial phenotype. Our data indicate a subtle role of nonendothelial PECAM-1 in acute allograft rejection. Although deletion of PECAM-1 could not prevent rejection, it should be further evaluated as a therapeutic target in more complex settings with concomitant immunosuppression or during chronic rejection.