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PubMed2003

Massive immune hemolysis after non-myeloablative allogeneic peripheral blood stem cell transplantation with minor ABO-incompatibility.

A 35-year-old male, blood group B, Rh(D)+ type, received an allogeneic peripheral blood stem cell (PBSC) transplant after a non-myeloablative regimen of fludarabine and cyclophosphamide for resistant gammadelta cutaneous T-cell lymphoma (CTCL). The donor was his HLA-identical brother, blood group O, Rh(D)+ type. Graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine alone. On day +8, massive immune hemolysis occurred, followed by acute renal failure. Hemodialysis was performed eight times until recovery of renal function on day +24. The risk of delayed immune hemolysis after non-myeloablative allogeneic PBSC transplantation with minor ABO-incompatibility must be considered.

ABO Blood-Group System↗

PubMed2004

Pharmacodynamics in the development of new immunosuppressive drugs.

Over the past 10-20 years a number of immunosuppressive drugs, such as cyclosporine A, tacrolimus, sirolimus, or mycophenolate mofetil have been approved for clinical use and have been highly successful in preventing or delaying graft rejection. Nevertheless, there is an incessant need for better and safer drugs to improve short-term and long-term outcomes following transplantation. A number of low-molecular-weight molecules that interfere with immune cell functions are in development. These include molecules that inhibit the janus protein tyrosine kinase JAK3, compounds that alter lymphocyte trafficking (the sphingosine-1-phosphate receptor antagonist FTY720), and new malononitrilamides (FK778). All seem to show promising therapeutic potential. Among the biologic agents, there are high expectations for antibodies or recombinant chimeric molecules targeting costimulatory surface molecules or pathways involved in the migration of immune cells. The list of such targets includes the ligand pairs CD28:B7, CD154:CD40, LFA-1:ICAM-1, ICOS:B7RP-1, and VLA-4:VCAM-1. However, the clinical development of drugs for transplantation has proved to be difficult, complex, and time consuming. Therefore, newly emerging drug candidates will also demand better methods for monitoring their efficacy as well as their side effects in vivo. Pharmacokinetics (PK) and pharmacodynamics (PD) are complementary approaches used to select drugs on the basis of their in vivo efficacy as well as safety. Whereas PK monitors the handling of the drug by the body, PD focuses on the biologic effect of the drug on its target. Therefore, PD studies of in vivo efficacy are useful for clinical decisions to determine the optimal dose and type of immunosuppressant. At the preclinical stage, PD is aimed at accelerating the selection of lead compounds via PD-controlled trials in animals. Moreover, PD can help to discover new mechanisms of action for a drug or a drug candidate. However, its full potential has not been used, mainly because of laborious and time-consuming methodology. This review focuses on established and novel PD/PK approaches to assess immunosuppressive compounds in the context of new evolving drugs or drug combinations.

Animals↗

PubMed1980

Spontaneous rupture of cadaver kidney allotransplants: how successful is a repair? Report of 22 cases and review of the literature.

Spontaneous rupture of the transplanted cadaver kidney is not rare in the early posttransplant period. Experience with this complication in 22 of 364 kidney transplantations performed from 1968 to 1978 is reviewed. Rupture is associated with typical symptoms and immediate exploration is mandatory. If the diagnosis and surgical repair is delayed for more than 24 h, the outcome is poor. This study emphasizes the possibility and necessity of conservation and repair of the ruptured allograft. In 15 out of 22 cases of rupture, graft repair was performed and normal graft function could be restored with long-term success in 11 of the 15 cases.

Cadaver↗

PubMed1998

Centralization of histocompatibility laboratories: impact on organ allocation efficiency and outcomes of cadaveric renal transplantation.

This project was undertaken to determine whether centralization of histocompatibility laboratory services for renal transplants performed within eastern Pennsylvania could improve the efficiency of allograft allocation and short-term allograft function. A nonconcurrent cohort study was performed comparing renal allografts transplanted between September 15, 1993, and September 14, 1994, to those transplanted between September 15, 1994, and September 14, 1995. All allografts were procured and allocated by the Delaware Valley Transplant Program, the organ procurement agency in eastern Pennsylvania. Cold preservation time and delayed allograft function were used to measure efficiency of allograft allocation and short term allograft function, respectively. The mean cold preservation time was reduced from 25.08 hours to 20.68 hours (P < 0.001). The percentage of delayed allograft function was 19.9 and 17.4 for the pre- and postcentralization groups, respectively (P = 0.5). Therefore, centralization of histocompatibility tissue typing was a regionally effective process intervention for reducing cold preservation time without adversely impacting short-term graft function. The magnitude of this reduction varied between individual centers. Further investigation is required to determine the effect on long-term allograft function and system wide costs.

Adult↗

PubMed1996

Cryopreserved anterior cruciate ligament allografts in a canine model.

This study was done to determine the clinical and biomechanical properties of cryopreserved anterior cruciate ligament allografts at 3, 6, 9, and 24 months after transplantation. A companion study of autografts was done to evaluate the effects of the surgical procedure and preservation on the tissue. The knee joints of 69 mongrel dogs (allograft n = 34, autograft n = 35) weighing 17 kg to 25 kg were grafted. Biomechanical results showed that maximum load was less in allografts than in autografts at each time interval. Deformation and slope were not significantly different between allograft and autograft. An apparent delay in revascularization and cellular repopulation was found in allografts compared with autografts, and collagen type I/type III ratios were similar in both grafts. DNA analysis indicated complete replacement of DNA in the graft by the host. Allografts provide adequate functional stability for daily activities in the canine model up to 2 years after transplantation. Biomechanical properties were relatively poor in allografts, which may lead to failure under more strenuous activity. The biologic similarity to autografts may indicate future remodeling potential.

Animals↗

PubMed1987

The role of T4+ and Ly-2+ cells in skin graft rejection in the mouse.

The role of the different T cell subsets (T4+ or Ly-2+) cells in the rejection of murine skin grafts was examined using the in vivo injection of monoclonal antibodies. The rat antimouse monoclonal antibodies used were shown to be active in vivo and to successfully deplete T4+ or Ly-2+ cells. H-2 mutant strains were used so that class I or class II MHC antigens could be studied in isolation; non-H-2 antigenic differences were also examined. The results were clear: (A) for class I antigens, Ly-2+ but not T4+ cells caused rejection; (B) for class II antigens, T4+ and Ly-2+ cells were both separately involved (additive studies indicated the unlikely involvement of Ly-2+T4+ cells); (C) for non-H-2 antigens, T4+ and not Ly-2+ cells were involved. In sensitized mice only anti-T4 antibodies caused any prolongation--for a class II difference. Our results relate strictly to phenotype and we have not measured cytotoxic or delayed-type hypersensitivity (DTH) (or IL-2 secretion) of cells in the graft causing rejection; nonetheless for class II antigens, anti-T4 treated mice had impaired in vivo DTH responses and the mediator of the DTH response to major histocompatibility complex (MHC) antigens is T4+; for class I antigens, DTH responses were not easily measured but mice with depleted DTH response were still able to reject grafts with a class I antigenic difference. The studies show that Ly-2+ cells, alone, can lead to graft rejection (for class I antigens) and T4+ cells alone (for non-H-2 antigens) can do the same. For class II antigens, T4+ cells are likely to influence the generation of Ly-2+ effector cells, although the precise mechanism is not clear. The studies therefore show that there is no special cell surface phenotype associated with graft rejection; rather the antigens presented dictate which cells are involved. How these cells function in the graft has yet to be demonstrated.

Animals↗

PubMed2001

Functional recovery in chronic paraplegic rats after co-grafts of fetal brain and adult peripheral nerve tissue.

BACKGROUND: In recent years, experimental studies have sought some type of functional improvement in traumatic paraplegia by transplanting neural tissue into the injured spinal cord. The aim of this work is to study the possibility of functional recovery in chronic paraplegic rats after co-transplantation of fetal cerebral tissue and adult peripheral nerve tissue. METHODS: Seventy adult female Wistar rats were subjected to spinal cord injury at the T6-T8 level, causing complete paraplegia. Three months later, in 50 rats (grafted group) the injured spinal cord tissue received a graft of fetal brain cortex associated with crushed adult peripheral nerve. All the animals (grafted and control groups) were subjected to daily rehabilitation procedures from the first week after the injury, and evaluated weekly for motor and sensory recovery. Statistical analysis of different behavioral data between control and grafted animals was performed using the Kruskal-Wallis ANOVA and the nonparametric Wilcoxon test. RESULTS: Between 8 and 12 months after transplantation, progressive signs of functional recovery were observed in the grafted animals, associated with an increase in muscle mass in the lower extremities, findings that were significantly different from those in nongrafted animals (p < 0.05). At this time, donor cerebral tissue is integrated into previously injured spinal cord and results in formation of bundles of nerve fibers that emerge from the area of the transplant and surround the spinal cord beneath the lesion. CONCLUSIONS: Delayed co-transplantation of fetal cerebral tissue and peripheral nerve tissue can be used to achieve anatomical remodeling and long-term functional recovery in rats rendered paraplegic as result of severe spinal cord injury. These findings support the possibility of functional recovery after chronic traumatic paraplegia.

Analysis of Variance↗

PubMed1975

Age-related changes in cell-mediated immunity in BALB/C mice.

The effect of increasing age on various tests of cell-mediated immunity was investigated in BALB/c mice both in vitro and in vivo with four different assay systems. The following results were obtained. 1) In contact sensitivity to DNFB, old mice (age 60 to 80 weeks) showed no differences in sensitization when compared to young adult mice (age 8 to 12 weeks). (In contrast, old NZB/W mice showed impaired contact sensitization when compared with young NZB/W MICE.)2) Unlike the reaction in contact sensitivity, cells from old BALB/c mice were defective in eliciting a graft-vs-host reaction. This was true also when a partially purified population of T cells was transferred. 3) In the mixed lymphocyte reaction, cells from old mice were as efficient or better than cells from young adult BALB/c mice in responding to or stimulating allogeneic cells. 4) Responses to PHA and Con A (Both T cell mitogens) were greatly reduced when old cells were cultured as compared with cells from young adult mice. Thus, we have found that within the same batch of mice, increasing age was associated with increased capabilities in some measures of cell-mediated immunologic function and decreased capabilities in other measures of the same.

Aging↗

PubMed1992

Reinnervation of denervated skeletal muscles by grafted dorsal root ganglion.

We examined whether or not the cervical dorsal root ganglion (DRG) of the rat, when isografted and connected to the distal stump of the severed common peroneal nerve, could survive, project axons to the denervated leg muscles, and exert beneficial influences to delay the degeneration of the denervated muscles. Rats in which the muscles were similarly denervated but no DRG was grafted served as the control. After a postoperative period of 72 to 286 days, histological study showed that nerve cells at the superficial part of the grafted DRG survived. Indirect electrical stimulation via the distal stump of the common peroneal nerve produced no contraction of the muscles, indicating that no functional neuromuscular contacts had been reestablished. Direct stimulation of the denervated muscles did elicit contraction, and the isometric twitch and tetanic tensions were significantly much higher in the experimental rats with a grafted DRG than in the control rats. Cholinesterase-silver staining indicated the presence of axons in the denervated muscles, but the axons did not terminate on endplates. Compared with the control muscles, the experimental muscles had significantly more axons, and had atrophied less as indicated by muscle wet weight and histological appearance. These results indicate that the sensory axons can delay the weakening and atrophy of muscles after denervation. We suggest that the sensory axons may exert certain trophic influence on the denervated muscle fibers, though the actual mechanism is unknown.

Animals↗

PubMed2005

Glabrous dermal grafting: a 12-year experience with the functional and aesthetic restoration of palmar and plantar skin defects.

BACKGROUND: Glabrous skin on the palmar aspect of the hands and the plantar aspect of the feet has special attributes. These attributes define the skin on the palm, fingers, and sole as functionally and aesthetically different from skin on other parts of the body. When there is a glabrous skin defect, it should be replaced with similar skin to restore function and aesthetics. The authors report their 12-year experience with the technique of glabrous dermal grafting for the reconstruction of palmar and plantar skin defects. METHODS: From 1992 to 2004, 13 patients with 14 defects underwent glabrous dermal grafting of either palmar or plantar defects. Defects included nine hand and five foot defects. Causes included nine acute burns, one secondary burn reconstruction, two delayed reconstructions of traumatic injuries, one congenital nevus, and one malignant melanoma. Donor sites included 12 glabrous dermal grafts from the foot and two from the hand. RESULTS: Follow-up ranged from 1 month to 65 months. All glabrous dermal grafts demonstrated complete epithelialization and no incidence of complete loss. There was return of sensation without hyperkeratosis or breakdown. The grafts demonstrated good color match with the surrounding skin. The donor site healed without complications, and there were no incidences of significant hypopigmentation, hyperpigmentation, or hypertrophic scarring. CONCLUSION: Glabrous dermal grafting of palmar and plantar defects is the ideal way of reconstructing glabrous skin to restore both function and aesthetics and minimize donor-site morbidity.

Adolescent↗

PubMed2004

[Advances and limitations of liver transplantation in Germany].

Orthotopic liver transplantation (OLT) is now an established therapy for end stage liver disease as well as acute liver failure. Improvements in surgical techniques, meticolous selection of transplant candidates and advances in immunosuppression have markedly increased patient and graft survial. The demand for organ grafts has continuously increased. Living donor organ transplantation omits the problem of organ shortage with prolonged waiting times for OLT and the likelihood of disease progression especially in tumor patients. Advanced liver disease related to chronic viral hepatitis is one of the primary indications for OLT worldwide. Combination therapy with hepatitis B immunoglobulin and lamivudine has been widely adopted as an effective prophylactic treatment regimen against recurrent HBV infection. Reinfection of the allograft is obligate in viremic post transplant patients with HCV infection. However the use of pegylated interferon in combination with ribavirin holds promise for delaying rapid progression of HCV infection in the allograft and the need for retransplantation. Recurrence of PBC, PSC and autoimmune hepatitis affects between 20 % and 30 % grafts at 10 years but appears to have little impact on long-term graft function and survival. In patients with hepatocellular carcinoma fulfilling strict selection criteria for OLT, 5 year survival rates of approximately 75% have been reported.

Antiviral Agents↗

PubMed1982

Maturation of functional T-lymphocyte subpopulations in the rat.

The T-lymphocyte differentiation alloantigens, A.R.T.-1 and A.R.T.-2 were used to follow the functional development of these cells in the rat. Delayed hypersensitivity and lymphocytes cytotoxic for allogeneic tumor cells were present in adoptively transferred recipients by 3 wk postirradiation and fetal liver reconstitution. However, these animals did not regain appreciable GvH potential until 7.5 wk postreconstitution. Normal percentages of A.R.T-1 lymphocytes were observed at all times in the spleen and lymph nodes of these animals, whereas, below normal numbers of A.R.T-2 lymphocytes were observed up to 7.5 wk postreconstitution. Depletion experiments using specific anti-A.R.T. sera demonstrated that the proliferative response to PHA and the cytotoxic lymphocyte response to alloantigens were reduced after treatment with anti-A.R.T.-1, but not with anti-A.R.T.-2. In contrast, the GvH potential of lymph node cells was reduced by treatment with either anti-A.R.T.-1 or anti-A.R.T.-2 serum plus complement. The use of these A.R.T. alloantisera in the rat has greatly facilitated the establishment of differentiation patterns for functional T lymphocytes and has resulted in the association of specific functional T-cell subpopulations with characteristic surface alloantigens.

Animals↗

PubMed2000

Implantation of bioactive growth factor-secreting rods enhances fetal dopaminergic graft survival, outgrowth density, and functional recovery in a rat model of Parkinson's disease.

One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.

Animals↗

PubMed1996

Timing of fiber arrival and dennervation of postsynaptic neurons is required for restoration of visual perception by regenerating axons.

Axotomized CNS neurons, whose regenerating axons are guided to their natural target areas in the brain with the aid of peripheral nerve grafts, are capable of establishing synaptic contacts with normal morphological and electrophysiological properties. The present study was undertaken to analyse the functional significance of the reestablished synaptic contacts made by these regenerated retinofugal neurons. Adult rats were trained in a T-maze to obtain a food reward with the aid of visual cues. One of their optic nerves was transected and the regenerating axons were guided into the optic tract with a peripheral nerve graft, in order to enable them to reinnervate the superior colliculus (SC) and thalamus. Postoperative testing of the animals showed a drastic improvement of visual perception. The protocol of dennervation of the SC (prior to, simultaneous or with a delay with respect to fiber arrival) determined the performance of the animals. Rats belonging to the first two groups performed almost as well as they did prior to the transplantation. The functional integrity of the retina was assessed by electroretinography (ERG) which revealed typical rod spectral sensitivity at 380 and 500 nm, but reduced responsiveness to illumination. In accordance, neuroanatomical assessment of the retinal ganglion cells revealed that about 15% of the axotomized neurons contributed to regeneration of axons. These findings show that a restricted population of retinofugal axons of capable of restoring higher visual functions such as light-discrimination-behaviour in the adult rat. Prerequisites for the restoration of visual perception are first the preservation of the intraretinal integrity, and second the temporal matching of fiber arrival and dennervation of postsynaptic neurons.

Animals↗

PubMed2001

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Animals↗

PubMedDate not supplied

Early vascular grafting to prevent upper extremity necrosis after electric burns: additional commentary on indications for surgery.

Early vascular grafting has been used to reestablish circulation to the hand in the treatment of electric injuries of the wrist with arterial damage. Since 1972 this therapy has yielded good results by preventing necrosis of the injured hand and by helping to maintain function. However, the indications and timing for performing this operation still are poorly defined. The surgeon is faced with the difficult task of determining whether the injury is severe enough to affect distal circulation and thereby lead to necrosis. The lack of reliable clinical signs is chiefly responsible for this difficulty; however, the potential for delayed thrombosis of vessels complicates the problem. In this article, indications for early vascular grafting in an electrically injured wrist are discussed based on recent clinical experience, with emphasis on the use of arteriography. A case history involving electric burns of both upper extremities is presented as an illustration.

Angiography↗

PubMed1998

The rectus abdominis myocutaneous flap: modifications, complications, and sexual function.

BACKGROUND: Vaginal, perineal, and pelvic floor reconstruction is being performed with increasing frequency in conjunction with radical pelvic surgery. Although the vertical rectus abdominis myocutaneous flap is ideally suited to such procedures, little information exists regarding risks or complications associated with it. METHODS: A chart review of all patients who underwent this procedure at two institutions was performed, and the results were compared with existing series. Surviving patients were asked to describe their satisfaction with the procedure and their sexual function. RESULTS: Between 1990 and 1997, 22 patients underwent placement of a rectus abdominis myocutaneous flap for vaginal/pelvic floor reconstruction, 21 (95.5%) at the time of pelvic exenteration. Attachment of the graft was complete in 20 patients (90.9%) and partial in 1 (4.5%), and 1 patient experienced complete loss that resulted in total vaginal stenosis. Four patients (18.2%) developed mild vaginal stenosis that was corrected with dilators. Donor site complications included wound separation (above the fascia) in three patients and one delayed abdominal closure. There were no cases of bowel obstruction, dehiscence, hernia, or death. The only statistically significant identifiable risk factors for graft necrosis included prior abdominal surgery and operative time. Thirteen of 22 (59.1%) of the patients are cancer free (median progression free interval, 42.2 months), 11 (84.6%) of whom reported having had vaginal intercourse since surgery. CONCLUSIONS: The rectus abdominis myocutaneous flap can be safely used with excellent results and acceptable morbidity, and in this series it restored sexual function in the majority of cancer survivors. Because previous abdominal surgery (transverse incisions or colostomy) may compromise blood supply to the flap, alternative sites should be considered in such cases.

Adult↗

PubMed1990

Treatment with total lymphoid irradiation, cyclosporin A and a monoclonal anti-T-cell antibody in a hamster-to-rat heart transplantation model: graft survival and morphological analysis.

Treatment with preoperative total lymphoid irradiation and post-transplant cyclosporin A has been shown to have a synergistic effect on graft survival in allo- and xenotransplantation. Specific monoclonal antibodies against T cells and T cell subpopulations could offer new ways of preventing graft rejection in xenotransplantation. Graft survival and histology were examined after total lymphoid irradiation plus cyclosporin A treatment versus cyclosporin A plus a monoclonal antibody in a concordant, heterotopic, hamster-to-rat heart transplantation model. Preoperative total lymphoid irradiation was given at a dose of 1.25 Gy, 12 times over a period of 3 weeks. Cyclosporin A at a dose of 12.5 mg/kg per day was administered perorally and OX-19, a pan T cell monoclonal antibody, was given as intraperitoneal injections at doses of 100 micrograms or 500 micrograms/kg per day from day 0 until graft rejection. While total lymphoid irradiation alone prolonged graft survival to 9.4 days, total lymphoid irradiation plus cyclosporin A extended graft survival to a mean of 22 days. Cyclosporin alone or combined with the monoclonal antibody could not increase graft survival significantly when compared to untreated animals, which rejected their grafts within 3.7 days. Vascular rejection was the characteristic morphological finding, even after some weeks of excellent graft function. In conclusion, total lymphoid irradiation and cyclosporin A had a synergistic effect on graft survival in this concordant xenotransplantation model, although recent impressive results from other groups could not be reproduced. Total lymphoid irradiation combined with cyclosporin A appears to delay a primary humoral graft rejection, while the mechanism of rejection, judged by histology, stays the same.

Analysis of Variance↗