Vascularized whole knee joint allografts in rabbits immunosuppressed with cyclosporin A

Summary 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.

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Zusammenfassung Für die Entwicklung eines operativen Modells wurden ganze Kniegelenke — einschließlich des distalen Femurendes, des proximalen Tibiaendes und der Gelenkkapsel — mit einem Gefäßstiel isoliert, aus der Gliedmaße herausgehoben und an der gleichen Stelle wieder reimplantiert. Eine stabile Fixation der Knochen wurde mit zwei Miniplatten an Tibia und Femur durchgeführt. Die Revaskularisation des Kniegelenkes wurde durch End-zu-End-Anastomosen der Poplitealgefäße mit den standardisierten mikrochirurgischen Techniken erreicht. Die Gefäß- und Nervenversorgung von Unterschenkel und Fuß wurden erhalten. Insgesamt wurden dann 21 vaskularisierte Ganz-Knie-Transplantationen mit einem mikrochirurgisch versorgten Gefäßstiel zwischen zwei inkompatiblen Hasenrassen vorgenommen. In einer Kontrollgruppe von sechs erwachsenen Tieren wurden keine Immunosuppressiva verabreicht. Zwei dieser Gelenke wurden nach 1 Woche entnommen und zeigten offene Poplitealarterien. Die restlichen vier Gelenke wurden nach 2–3 Wochen entnommen, als sie Zerfallserscheinungen aufwiesen und arteriographisch ein Verschluß der Poplitealgefäße festgestellt wurde. Bei acht erwachsenen Empfängern von allogenen Transplantaten wurde eine immunosuppressive Behandlung mit Cyclosporin A (CyA) mit 15 mg/kg pro Tag durchgeführt. Bei einem Allotransplantat trat nach 10 Tagen ein Versagen wegen einer Femurfraktur auf. Bei keinem der übrigen sieben Transplantate kam es zu einer akuten Abstoßungsreaktion, und drei Transplantate zeigten nach 100 Tagen arteriographisch offene Gefäße und lichtmikroskopisch vitalen Knochen und Knorpel. In einer anderen Gruppe wurden sieben allogene Kniegelenke bei wachsenden Kaninchen transplantiert und mit CyA immunosuppressiv behandelt. Wiederum trat keine akute Abstoßung auf, und nach 90 Tagen zeigten drei der sieben Allotransplantate arteriographisch offene Gefäße, Wachstum in Röntgenserienaufnahmen und lichtmikroskopisch vitalen Knochen und Knorpel. Diese Pilotstudie legt nahe, daß CyA ein nützliches Immunosuppressivum darstellt für die Untersuchung vaskularisierter Knochenund Knorpeltransplantate. Außerdem zeigt die Studie, daß eine experimentelle Transplantation von allogenen Epiphysenplatten bei Kaninchen möglich ist.

     

Limb allografts in rats immunosuppressed with cyclosporin A

The role of cyclosporin A in transplantation of composite tissue for potential reconstructive purposes is examined in the rat hind limb transplant model. Two inbred rat strains were utilized. Brown ACI rat hind limbs were transferred to the dorsum of white Lewis rats with microvascular anastomoses. Twenty transplants were divided into four groups for postoperative immunosuppression: control, no cyclosporin; 7 days of cyclosporin; 21 days of cyclosporin; and continuous cyclosporin from 44-113 days. Hemagglutination and antibody titers were measured. Clinical evaluation and histologic examination at sacrifice were performed and rejection graded. Cyclosporin A has been successful in suppressing rejection in composite allograft transplant across defined major histocompatability barriers. Rats treated with cyclosporin A for a short period of time showed signs of rejection after discontinuation of therapy. Five animals treated continuously on cyclosporin A for up to 113 days showed no sign of rejection clinically, histologically, or immunologically.     

Growth of forelimb allografts in young rabbits immunosuppressed with cyclosporine

Seventeen forelimbs were transplanted orthotopically from young Dutch rabbits to young New Zealand rabbits treated with cyclosporine. The transplanted limbs demonstrated significant bone growth. The growth in the transplanted limbs was about 75 to 80% of that observed in the unoperated limb. The long bones of the 3 longest surviving rabbits (133 days, 150 days, 150 days) studied radiographically demonstrated increases in length over their original lengths (humerus 22%, ulna 26%, and radius 31%). Hair and nail growth were noted at about day 10. Response to pain stimuli (withdrawal of forelimb) and functional use (ambulation with 50% weight bearing) was seen at two to three months. Permanent survival was not achieved because of a species-specific toxic wasting syndrome from cyclosporine.     

Electrophysiologic evaluation of peripheral nerve regeneration through allografts immunosuppressed with cyclosporin

A model was designed to evaluate the long-term in vivo electrophysiology of rat peripheral nerve transplants. The application of this model was demonstrated using cyclosporin (CSA) immunosuppression of recipient animals to facilitate peripheral nerve regeneration through nerve allografts. Isogenic Brown Norway (BN) rats [RT1n] were divided into three groups: two received Lewis (LE) rat [RT1l] allografts and one received BN isografts. One allograft recipient group received CSA immunosuppression for the duration of the investigation (150 days). Successful nerve regeneration in the isograft and the immunosuppressed allograft recipient groups was determined by immunohistochemical methods and serial in vivo electrophysiologic techniques to measure nerve conduction velocity and evoked compound muscle action potential amplitude. Statistical analysis of these results indicate that: (a) CSA immunosuppression of peripheral nerve allograft recipients facilitates peripheral nerve regeneration which is indistinguishable from isograft recipient controls at the functioning axon level; and (b) in vivo electrophysiologic monitoring in this model is particularly useful for long term peripheral nerve transplantation studies permitting serial assessment of regeneration with little morbidity.     

Effects of cyclosporin A and predegeneration on survival and regeneration of peripheral nerve allografts in rabbits

Axonal regeneration across 64 median nerve grafts in 34 rabbits was studied histologically to determine the optimal conditions for nerve allografting. Axonal regeneration across allografts in cyclosporin A-treated animals was satisfactory, but it occurred more slowly and with more inflammation and fibrosis than in autografts. Without immunosuppression, fresh allografts were rejected. However, in immunocompetent hosts, allografts rendered less immunogenic by predegeneration were not rejected, and axonal regeneration occurred. The combination of cyclosporin A and nerve graft predegeneration produced the most substantial axonal regeneration, comparable to autografts. The observations suggest that nerve allograft survival may be optimally effected by cyclosporin A treatment coupled with reduction in the immunogenicity of the grafts, such as by predegeneration.     

A modified vascularized whole knee joint allotransplantation model in the rat

Previous papers have shown surgical neoangiogenesis to allow long‐term bone allotransplant survival without immunosuppression. Whole joint composite tissue allotransplants (CTA) might be treated similarly. A novel rat knee CTA model is described for further study of the roles of neoangiogensis in joint allotransplant survival and adjustment of immunosuppression. Microvascular knee CTA was performed in nine rats across a major histocompatibility barrier with both pedicle repair and implantation of host‐derived arteriovenous (“a/v”) bundles. In the control group (N = 3), the pedicle was ligated. Immunosuppression was given daily. Joint mobility, weight‐bearing, pedicle patency, bone blood flow, and sprouting from a/v bundles were assessed at 3 weeks. All but the nonrevascularized control knees had full passive motion and full weight bearing. One nutrient pedicle thrombosed prematurely. Blood flow was measurable in transplants with patent nutrient pedicles. Implanted a/v bundles produced new vascular networks on angiography. This new rat microsurgical model permits further study of joint allotransplantation. Patency of both pedicles and implanted a/v bundles was maintained, laying a foundation for future studies. © 2010 Wiley‐Liss, Inc. Microsurgery, 2010.     

Gastrointestinal perforations in renal transplant recipients immunosuppressed with cyclosporin

Gastrointestinal perforations frequently represent a lethal complication of immunosuppression. Of 325 renal transplant recipients treated with cyclosporin (CsA), 4 patients (1.2%) developed gastrointestinal perforation: 1 from gastric ulcer and 3 from colonic diverticula. All patients underwent operative treatment and all survived without complications. Three patients maintained a well-functioning allograft. In comparison to azathioprine, CsA does not seem to greatly affect the immune response to bacterial infections, thus representing a considerable advantage in the management of serious gastrointestinal complications.

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Resumen Las complicaciones gastrointestinales no son raras en pacientes con transplante renal bajo inmunosupresión con azatioprina-prednisona, especialmente las perforaciones de úlcera péptica o de enfermedad diverticular del colon, las cuales frecuentemente vienen a significar una complicación letal de la inmunosupresión. El manejo de estas complicaciones que ponen en peligro la vida del paciente, comprende descontinuar la inmunosupresión con abandono del injerto. Sinembargo el nuevo agente inmunosupresor, la ciclosporina (CsA), un endecapéptido fungal de novedosa estructura química, exhibe una acción inmunosupresiva más específica sobre las células T que la azatioprina, dejando casi intacta la respuesta de células B a la infección bacteriana. Estos factures deben hacer que las perforaciones gastrointestinales en pacientes bajo CsA sean eventos menos desastrosos. De 325 pacientes receptores de transplante renal tratados con CsA, 4 (1.2%) desarrollaron perfora ción: 1 por úlcera gástrica y 3 por divertículos colónicos. Todos fueron sometidos a tratamiento quirúrgico y todos sobrevivieron sin complicaciones. Tres mantuvieron su aloinjerto funcionando bien. En comparación con la azatioprina, la CsA no parece afectar mayormente la respuesta inmune a las infecciones bacterianas, lo cual representa una ventaja de significación en el manejo de complicaciones gastrointestinales serias.

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Résumé Les perforations digestives représentent souvent une complication fatale de l'immunosuppression. Chez 325 transplantés rénaux traités par la cyclosporin A (CsA), 4 (1.2%) ont présenté une perforation digestive; 1 cas de perforation d'ulcère gastrique, 3 cas de perforation de diverticule colique. Les 4 malades furent opérés avec succès. Trois d'entre eux ont gardé une fonction rénale normale. Par comparaison avec l'Azathioprine la CsA ne paraît pas affecter considérablement la réponse immunitaire à l'infection bactérienne et de ce fait elle présente un avantage considérable pour traiter les complications gastro-intestinales sérieuses.

     

Subrenal capsule assay in normal mice immunosuppressed by cyclosporin A

The subrenal capsule assay in normal mice has more advantages to evaluate sensitivities of anticancer agents than other assays in vivo. However, this method has difficulties because mice reject human tumor grafts by their immune reaction. We examined three methods of immunosuppression in mice; radiation, administration of cyclophosphamide and that of cyclosporin A. The administration of cyclosporin A suppressed host reactions most effectively among the three, and the human tumor grafts in subrenal capsules grew well. We also investigated the intervals of administration and the doses of cyclosporin A in order to evaluate drug response. The minimal dose of cyclosporin A which inhibited host reactions was revealed to be 50mg/kg/day administered subcutaneously to mice. Then the adequate dosage of each anticancer drug for this assay system was investigated so that the body weights of mice do not decrease more than 20%, and the following doses were determined; Mitomycin C: 5mg/kg; Cisplatinum: 4mg/kg; Cyclophosphamide: 100mg/kg and 5FU: 90 mg/kg.     

Survival of nerve allografts in sensitized rats treated with cyclosporin A

This study examined the effect of immunosuppressive treatment with cyclosporin A (Cy-A) on the survival of nerve allografts in sensitized rats. Nerve- or skin-sensitized untreated rats rejected a second nerve allograft of the same genotype as the first in an accelerated manner. In this situation, only a few host axons grew into the proximal 1 cm of a 4 cm-long nerve allograft. However, if sensitized rats were given Cy-A (10 mg/kg daily), the second nerve allograft survived, and numerous host axons regenerated through the 4-cm length of the allograft. These results indicated that Cy-A was an effective immunosuppressive agent in sensitized rats. We conclude that, in rats, donor-specific sensitization is not a contraindication to the use of nerve allografts to aid in the repair of injured nerve when Cy-A is used for immunosuppression.     

Vascularized knee joint transplantation in man: a report on the first cases

Abstract Four transplantations of an allogeneic vascularized human knee joint were performed at the Trauma Center Murnau between April 1996 and July 1997.The indication for the procedure was the total loss of the knee joint including the extensor apparatus due to severe trauma. These were the first transplants of this type. Management of patients started with closure of soft-tissue defects. After successful completion, stabilization was achieved with femoral and tibial nails plus a temporary arthroplasty. ABO compatibility and a negative cross-match were the main criteria for selecting patients for transplantation. Interlocking compression nails were used for osteosynthesis. Vascular anastomoses between graft and recipient vessels were established by the enD-to-side technique. Immunosuppression was started as a quadruple induction therapy for 3 days, then reduced to a two-drug maintenance therapy with cyclosporine and azathioprine. Six months posttransplantation the osteotomies were bridged by callus and the patients became completely mobile. Radiographic and histological examinations revealed vital graft tissue.     

A histo-morphometric study on peripheral nerve allografts in rats with cyclosporin A]

This investigation evaluates regeneration across peripheral nerve allografts in minor mismatch rats immunosuppressed with Cyclosporin A (CSA). Lewis(RT1(1)) rats were recipients of 20 mm sciatic nerve grafts from allogenic Fischer (RT1(1)) donors. The recipients were randomly allocated to CSA immunosuppressed or untreated groups. CSA was administered at a daily dose of 5 mg/kg by subcutaneous injection for 8 weeks. Two animals from each group were sacrificed at 2, 4, 6, 8 and 12 weeks after the operation, and bilateral sciatic nerves were resected. Until the 8th week, the CSA-treated group showed good vascularization and minimal scar formation. The regeneration was faster and better in the CSA-treated group than in the untreated group. At the 12th week, however, the CSA-treated group showed scarring in the grafted nerves and Wallerian degeneration in the distal nerves, whereas the untreated group showed increased vascularization and myelinated fibers. The results have demonstrated that CSA greatly facilitates the regeneration process across the nerve allograft whereas the discontinuation of CSA leads to reduction of the regenerated nerve fibers. These findings would indicate that the use of CSA is imperatively needed even in minor mismatch cases.     

Risk factors for second renal allografts immunosuppressed with cyclosporine

Second renal allograft survival rates are lower than those of primary allografts. For recipients immunosuppressed with azathioprine, prednisone, and Minnesota ALG (conventional immunosuppression), risk factors associated with decreased second graft survival have been identified: age greater than 40, cadaver donor, less than 6 months between primary graft loss and retransplantation, duration of primary graft function (6 months or 1 year, depending on the study), high peak panel-reactive antibody, number of human leukocyte antigen mismatches, and delayed graft function. In this study, we used a multivariate analysis to identify risk factors associated with decreased second graft survival in patients who did or did not receive cyclosporine. Results were compared with primary graft survival rates. Risk factors for patients receiving conventional immunosuppression were: (a) primary graft loss caused by rejection greater than or equal to 6 months (P = 0.01 vs. either rejection less than 6 months or nonimmunologic loss); (b) cadaver donor (P = 0.005 vs. living related); and (c) interval between primary graft loss and retransplantation of greater than or equal to 6 months (P = 0.05 vs. less than 6 months). For CsA, risk factors that most decreased second graft survival were: (a) primary graft loss caused by rejection less than 6 months (P = 0.11 vs. nonimmunologic loss); (b) conventional immunosuppression for the primary graft (P = 0.08 vs. CsA immunosuppression); and (c) a peak PRA of greater than or equal to 21 (P = 0.14 vs. peak PRA of 1-20). For second graft recipients immunosuppressed with CsA, primary graft loss to either rejection greater than 6 months posttransplant or nonimmunologic causes was not a risk factor for second graft survival. These data extend the recent reports of other investigators by identifying risk factors for retransplant recipients treated with CsA and by demonstrating that subgroups of patients in the retransplant population can be retransplanted without additional risk (i.e., their second graft survival rates are similar to primary graft survival rates). This may become more important if, in the future, organ distribution is based on graft survival data. If so, our data would support retransplantation in patients who are immunosuppressed with CsA, especially those who lost their primary graft to either rejection greater than or equal to 6 months posttransplant or nonimmunologic causes; who receive living related grafts; and who have a peak PRA of 1-20.     

Cerebromeningitis in immunosuppressed recipients of renal allografts.

The experience with cerebromeningitis in recipients of 769 renal allografts occurring over a 20-year period has been reviewed. Eighteen patients developed this complication; an incidence of 2.7%. Clinical manifestations were often subtle, although fever occurred almost universally. Primary risk factors included diabetes mellitus, use of high dose steroids both as maintenance immunosuppression and as treatment for acute rejection, and coincident infections or complications. The responsible organisms were fungi; the overall mortality rate 44%. By recognizing individual patient types who are at potential high risk for this complication, earlier diagnosis and more prompt and aggressive therapy has diminished the mortality dramatically in the last several years.     

Selective lymphoid irradiation and cyclosporin A in rat heart allografts

Short-term peritransplant treatment utilizing 2-dose ALG and 1-dose Palladium-109-hematoporphyrin (PD-H) for selective lymphoid irradiation (SLI) leads to donor-specific permanent acceptance of heart allografts in the Fisher to Lewis rat model. The same treatment significantly prolongs survival of hearts transplanted to strongly histoincompatable, presensitized, and xenogeneic recipients. The purpose of this study was to evaluate synergistic effects of short-term, low-dose cyclosporin treatment and SLI in an attempt to develop a nontoxic protocol utilizing peritransplant treatment for immune preconditioning with minimal subsequent immunosuppression. Single-agent treatment alone with cyclosporin, ALG, or Pd-H resulted in a maximal mean graft survival time (MST) of 33 days. Immunosuppression with 1-dose Pd-H, 2-dose ALG, and low-dose cyclosporin (5 mg/kg) for 14 days doubled the MST to 78 days. Use of therapeutic-dose cyclosporin (20 mg/kg), given for just 3 days, was also quite effective, MST of 57 days with SLI and 43 days with ALG, but toxic; 3 of 12 recipients died of infection with functioning grafts. These results demonstrate that the use of low-dose cyclosporin over a short interval, when combined with peritransplant SLI, is a highly effective and safe method for prolonging heart allograft survival.     

Vascularized bone allografts: an experimental study in dogs

This study attempted to re-establish vascularization to canine allograft bone by means of the introduction of a pedicle in the medullary canal with a capillary network. The experiment showed basically that the introduction of arteries and veins with a capillary network into the medullary canal of an allograft femur provided enough vascular supply to produce fibrous tissue and enough bone to cover preoperatively drilled holes, suggesting that the allograft "revives" with the introduction of a vascular supply.     

FK506和抗淋巴细胞血清诱导兔异体膝关节移植耐受的实验研究

目的　探讨短期使用FK5 0 6和抗淋巴细胞血清 (ALS)诱导兔同种异体膝关节移植嵌合耐受的作用。　方法　雄性大耳白兔作为供体 ,雌性新西兰白兔作为受体 ,施行同种异体异位膝关节移植 ,设单独使用ALS( 1ml/kg)组、单独使用FK5 0 6( 0 5mg/kg)组、联合使用FK5 0 6和ALS组及对照组。FK5 0 6和ALS在移植术前 1d开始使用 ,ALS连续使用 3d ,FK5 0 6连续使用 15d。观察移植物的存活时间 ,检测受体内供体血细胞嵌合率 ,进行组织切片检查。　结果　对照组平均存活 ( 13 6± 0 8)d ,单独使用ALS组为 ( 17 4± 1 8)d ,单独使用FK5 0 6组为 ( 2 3 8± 1 5 )d ,联合使用FK5 0 6和ALS组为 ( 4 0 4±2 9)d。联合使用FK5 0 6和ALS组的供体血细胞嵌合率停药后 3周稳定在 10 %以上。　结论　短期使用FK5 0 6和ALS可显著延长兔同种异体膝关节移植的存活时间 ,可维持 3周的嵌合耐受。     

Prolongation of intraperitoneal segmental pancreatic allografts in primates receiving cyclosporin A

In this study the efficacy of the new immunosuppressive agent, cyclosporin A (CYA), was examined in a model of segmental, intraperitoneal pancreatic allotransplantation with free duct drainage in totally pancreatectomized, outbred Chacma baboons. CYA, in doses of 25 to 50 mg/kg/day administered to recipients of heterotopic segmental (tail) allografts, produced a slight but significant prolongation of graft survival. CYA (25 to 85 mg/kg/day), administered orally after pancreatic transplantation gave daily serum trough levels of CYA that ranged from 300 to 600 ng/ml. Mean serum trough levels on the first postoperative day in recipients of 50 mg/kg/day were 121.1 +/- 61.6 ng/ml. There was a wide variation in daily serum trough levels exhibited between primates on the same daily oral dose, and there was no correlation between absolute serum trough levels of CYA and rejection. It is postulated that adequate serum CYA levels were not achieved by the oral administration of the drug to ensure allograft survival beyond 60 days in pancreatectomized recipients. Adverse effects occurred frequently and included anorexia, diarrhea, and tremors and were in direct proportion to the quantity of CYA required to prolong graft survival. Free duct drainage into the abdominal cavity frequently resulted in pancreatic ascites, which necessitated paracentesis, indicating that this method of duct drainage has limited clinical application. Although heterotopic autotransplantation or allotransplantation of the tail of the pancreas in the baboon was capable of maintaining normoglycemia in pancreatectomized baboons, glucose intolerance, reduced K values, and hypoinsulinemia were consistent findings during glucose tolerance tests, suggesting that an insufficient islet cell mass had been transplanted.     

Vascularized thymic lobe transplantation in miniature swine: I. Vascularized thymic lobe allografts support thymopoiesis

BACKGROUND: Vascularized thymokidney transplants have previously been shown to induce tolerance across major histocompatibility complex barriers. The ability to perform vascularized thymic lobe transplantation could permit such tolerance to be induced with any cotransplanted solid organ or tissue. For this reason, we have developed a technique for vascularized thymic lobe transplantation in miniature swine. METHODS: Thymic vessels (n=2) were anastomosed to the carotid artery and the external jugular vein of na?ve minor-mismatched recipients treated with a 12-day course of cyclosporine A (10 mg/kg/day). Graft survival and thymopoiesis were assessed by histology, immunohistochemistry, and fluorescence-activated cell sorting. Allele-specific antibodies 74-12-4 and pig allelic antigen (PAA) were used to distinguish donor and recipient cells. RESULTS: Allografts showed intact cortical and medullary structure posttransplantation, without evidence of rejection or ischemia. Recipient thymocytes repopulated the donor cortical thymus by POD30 and increased in the cortex and medulla by POD60. CONCLUSIONS: Our study demonstrates the technical feasibility of vascularized thymic lobe transplantation and the support of thymopoiesis by such transplants in a large animal model. This technique may offer a novel strategy to induce transplant tolerance across allogeneic and xenogeneic barriers, and to support long-term thymopoiesis in immunodeficient hosts.     

Reconstruction with autologous pasteurized whole knee joint I: experimental study in a rabbit model

 Hyperthermia-treated bone has been used for skeletal reconstruction after resection of malignant bone tumors, and more favorable results have been seen after pasteurization than after autoclaving or boiling. Pasteurization destroys malignant cells while preserving the bone-inducing property. All previous experimental models have studied replantation of bone segments, but reconstruction of joints is more important clinically. We studied the effects of extracorporeal hyperthermia on the reintegration of autologous whole knee joint grafts over a period of 16 weeks in a rabbit model. The whole knee joint was resected from 32 animals, heat-treated at 65°C for 30 min, and replanted. In the control group, resection and replantation were performed without heat treatment. Reintegration was assessed by macroscopic analysis, histology, histochemistry, and radiography. Reintegration of the pasteurized group showed excellent remodeling during the 16 weeks, similar to the control groups. Responses to the pasteurization and the subsequent reintegration of cartilage, menisci, and ligaments were similar at 4, 8, 12, and 16 weeks with no significant difference between the two groups, although cartilage degradation seemed to occur earlier in the study group than in the control group. These results suggest that pasteurization may be superior to other cell-lethal treatments for autotransplantation of the whole joint currently available. Received: May 16, 2002 / Accepted: October 7, 2002 Acknowledgments. This work was supported in part by Grants-in-Aid for Scientific Research (C)12671394 (H.W., K.T.) and (C)12671395 (H.W., K.T.) from the Ministry of Education, Science, and Culture, of Japan. Offprint requests to: H. Watanabe