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PubMed1978

Impact of blood transfusion on renal transplantation.

The relationship between transfusion of different preparations of blood, sensitization to HLA antigens and survival of subsequent kidney transplants was investigated in 90 consecutive recipients. HLA lymphocytotoxins in transplant candidates precluded or greatly delayed receipt of an allograft (p less than 0.0005). Furthermore, only 17% of such sensitized recipients had functioning grafts one year after transplantation compared to 57% survival for nonsensitized recipients (p less than .02). A small number of nonsensitized patients who were never transfused had surprisingly poor one year graft survival (25%). If frozen blood is used for transfusion rather than whole/packed RBC, the incidence of patient sensitization can be markedly reduced without subsequent compromise in transplant survival (51%). It is concluded that as a consequence of avoiding HLA sensitization by transfusion of frozen blood (processed by agglomeration), the period of hemodialysis required for potential graft recipients will be shortened and an increased proportion of potential recipients will be successfully treated by transplantation.

Blood Transfusion↗
PubMed1987

[Urinary diversions and intestinal grafts in renal transplantation in children. Report of 8 cases].

In a series of 400 transplantations, 8 children presented a severe lesion of the lower urinary tract requiring an intestinal graft to divert the urine or to replace the useless bladder: 4 cases of posterior urethral valves and 4 cases of neurogenic bladder. Four permanent urinary diversions and 4 bladder enlargements, including 3 temporary diversions, were performed. The sigmoid colon was used in 5 cases and the ileum was used in 3 cases. The preparation of the intestinal graft was always performed prior to the transplantation. The uretero-intestinal anastomosis included an antireflux device in 3 of the 8 cases. There were no deaths in this series. Three occlusions and 2 lymphoceles occurred in the immediate post-transplantation period, but were corrected by re-operation. Two cases of calculi occurred in the long term, one of which required operation. Moderate stenosis of the renal artery in one case resulted in systemic hypertension which was well controlled by medical treatment. An episode of acute pyelonephritis resolved rapidly with antibiotic treatment. Two cases of acidosis were corrected by salt supplementation. There was one case of early graft rejection on the 15th day and a delayed rejection after 18 months, leading to removal of the transplant. At the present time, 6 renal grafts function normally (75%) with a follow-up of 1 to 8 years.

Adolescent↗
PubMed2005

The effects of delayed nerve repair on neuronal survival and axonal regeneration after seventh cervical spinal nerve axotomy in adult rats.

It has been proposed clinically that delayed surgery after traumatic brachial plexus injury may adversely affect functional outcome. In the present experimental study the neuroprotective and growth-promoting effects of early and delayed nerve grafting following proximal seventh cervical spinal nerve (C7) axotomy were examined. The ventral branch of C7 spinal nerve was transected and axons projecting out of the proximal nerve stump were labelled with Fast Blue (FB). At the same time, the biceps brachii muscle was denervated by transecting the musculocutaneous nerve at its origin. Neuronal survival and muscle atrophy were then assessed at 1, 4, 8 and 16 weeks after permanent axotomy. In the experimental groups, a peripheral nerve graft was interposed between the transected C7 spinal nerve and the distal stump of the musculocutaneous nerve at 1 week [early nerve repair (ENR)] or 8 weeks [delayed nerve repair (DNR)] after axotomy. Sixteen weeks after nerve repair had been performed, a second tracer Fluoro-Ruby (FR) was applied distal to the graft to assess the efficacy of axonal regeneration. Counts of FB-labelled neurons revealed that axotomy did not induce any significant cell loss at 4 weeks, but 15% of motoneurons and 32% of sensory neurons died at 8 weeks after injury. At 16 weeks, the amount of cell loss in spinal cord and dorsal root ganglion (DRG) reached 29 and 50%, respectively. Both ENR and DNR prevented retrograde degeneration of spinal motoneurons and counteracted muscle atrophy, but failed to rescue sensory neurons. Due to substantial cell loss at 8 weeks, the number of FR-labelled neurons after DNR was significantly lower when compared to ENR. However, the proportion of regenerating neurons among surviving motoneurons and DRG neurons remained relatively constant indicating that neurons retained their regenerative capacity after prolonged axotomy. The results demonstrate that DNR could protect spinal motoneurons and reduce muscle atrophy, but had little effect on sensory DRG neurons. However, the efficacy of neuroprotection and axonal regeneration will be significantly affected by the amount of cell loss already presented at the time of nerve repair.

Animals↗
PubMed1998

Late hypertension after liver transplantation: a comparison of cyclosporine and tacrolimus (FK 506).

Hypertension frequently develops early after liver transplantation when cyclosporine-based immunosuppression is used. However, initial experience with tacrolimus has suggested that its use leads to a lower early incidence of hypertension. In this study, the blood pressure status of patients treated with cyclosporine (n = 131) and those treated with tacrolimus (n = 28) was compared 24 months after liver transplantation. At this time interval, the prevalence of hypertension in the cyclosporine and tacrolimus groups were 82% and 64%, respectively (P < .05). For those patients who were hypertensive by 24 months, onset was delayed in the tacrolimus group compared with the cyclosporine group: 40% versus 71% and 73% versus 93% at 1 and 12 months, respectively (P < .05). Within the cyclosporine group, patients with hypertension were heavier than those with normal blood pressure, 84.7 +/- 1.8 versus 73.4 +/- 4.0 kg, respectively (P < .05). Within the tacrolimus group, hypertensive patients had lower glomerular filtration rates and higher renal vascular resistances compared with normotensive patients, 74 +/- 12 versus 47 +/- 6 mL/min and 15,711 +/- 2,445 versus 28,830 +/- 4,310 dyne/s/cm5/m2, respectively (P < .05). There were no within-group differences for age, gender, pretransplant history of hypertension, family history of hypertension, graft function, or daily doses of prednisone, cyclosporine, or tacrolimus. These results indicate that, compared with cyclosporine, the onset of hypertension after liver transplantation is delayed and less prevalent with tacrolimus. Additionally, hypertension is associated with increased body weight in cyclosporine-treated patients and with more severe renal dysfunction in patients receiving tacrolimus. The relationships of these findings to the development of posttransplant hypertension requires further study.

Blood Pressure↗
PubMed1994

[The transplanted kidney. Role of imaging in early non-functioning grafts].

Renal failure following transplantation can be classified in two groups: initial non function characterized by the absence of renal function after transplantation and delayed secondary non function after an initial improvement. In the first group, the most frequent etiology is an acute tubular necrosis (30 to 50% of the cases) which usually heals within three weeks. Arterial thrombosis are rare but of very bad prognosis. In the second group, the most frequent cases are acute rejection, urological complications, renal artery stenosis, urinary infections and cyclosporine, intoxication. Diagnostic imaging, and especially the color Doppler flow, is very effective in obtaining diagnosis. Vascular or urological complications are to be confirmed by contrasted opacifications. In the absence of vascular or urological obstruction renal failure must be related to a renal parenchymal disease. This may be acute tubular necrosis, a rejection, a pyelonephritis or a medicinal intoxication depending on clinical symptoms, the time of their apparition and the results of biological examinations.

Acute Kidney Injury↗
PubMed1987

Recovery of contact hypersensitivity responses following murine bone marrow transplantation: comparison of gamma-irradiation and busulfan as preparative marrow-ablative agents.

Bone marrow transplantation (BMT) is often followed by significant morbidity and mortality due to protracted immunodeficiency. We have hypothesized that the bone marrow-ablative regimen may delay the recovery of normal immune function following transplantation by impairing the interaction of host endothelial cells with circulating graft-derived lymphocytes. This report compares the relative effects of busulfan (an alkylating drug) and gamma-irradiation on the tissue-specific localization potential of lymphocytes and the eventual recovery of immune function within syngeneic murine transplant recipients. Localization of normal lymphocytes into peripheral lymph nodes of irradiated BMT recipients was markedly less (less than 50%) than in busulfan-treated or normal mice over the first 2 months post-BMT. This finding correlated with irradiation-induced endothelial cell edema and microvascular occlusions within lymphocyte-receptive areas of the nodal microvasculature. The effect of both preparative regimens on the recovery of contact hypersensitivity (CHS) was also analyzed. This response recovered more quickly (between 1 and 2 months) in busulfan-pretreated animals. Further experiments demonstrated that the decrease in CHS responsiveness appeared, in part, related to a depression in the capacity of lymphocytes to localize into skin sites of antigen deposition within irradiated mice. The impairment of tissue-specific lymphocyte localization may represent a novel mechanism by which whole body irradiation can contribute to delayed immunologic reconstitution following bone marrow transplantation.

Animals↗
PubMed1998

Hyperfiltration, creatinine clearance and chronic graft loss.

Chronic graft loss (CGL) may be caused by immunological- or hyperfiltration-mediated tissue destruction. If the hyperfiltration theory is correct, grafts from female donors given to heavy recipients, and having a relatively poor initial function, should suffer an accelerated rate of loss of function. 590 renal transplantations surviving more than 1 yr, including 171 cases of (CGL), were reviewed to identify causes of CGL. No overall influence of recipient or donor sex was found, but female donation resulted in lower acute graft loss and higher CGL. Warm ischemia affected CGL marginally, but cold ischemia < 12 h (excluding living donors) reduced CGL (35 vs. 53% at 10 yr, p < 0.05) and delayed function increased CGL (38% vs. 56% p < 0.001). Patients with a high urea production had high CGL (43% vs. 77%, p < 0.02). No overall effect of recipient weight was found; however 7 patients weighing > 90 kg all had CGL within 10 yr. Creatinine clearance was increasingly correlated to recipient weight (r = 0.23 at 1 yr, 0.38 at 10 yr, p < 0.001). For all years, change in creatinine clearance correlated with change in weight (p < 0.001). The most important factor predicting CGL was creatinine clearance, (> 80 ml/min: 6% at 10 yr; 20-40 ml/min 53%). However, at any level of creatinine clearance, patients with late CGL had a slower loss of renal function. Rate of change of renal function was proportional to creatinine clearance, but only for grafts surviving > 6 yr. Creatinine clearance rose between 3 mths and 2 yr; this rise indicated a good prognosis, was related to recipient weight and weight increase, and was reduced in older donors and cyclosporine treated patients. For patients with low clearance (< 60 ml/min), the increased CGL seen in patients with previous rejection episodes could be explained by their consequent lower clearance, but above this level, rejection episodes had an independent deleterious effect. These findings are compatible with hyperfiltration being the major cause of CGL after 6 yr. Before this immunological factors dominate. Good quality grafts respond to the increased protein load of heavy recipients with an increased GFR. Thus at any time, graft GFR is a function of protein-induced hyperfiltration, immunological graft destruction and hyperfiltration-mediated damage. Hyperfiltration-mediated renal damage is not a problem if the creatinine clearance is greater than 60 ml/min.

Adolescent↗
PubMed1991

Intraretinal grafting restores visual function in light-blinded rats.

In seeing rats light flashes inhibit acoustic startle reflexes at short lead times. In contrast, visually impaired (light-blinded) rats show an early phase of exaggerated reflex expression, revealing the presence of pathological visual processing, and then an aberrant late phase of delayed inhibition. Grafting fetal retinal cells into the damaged retina entirely removed reflex facilitation and restored a modest degree of properly timed and statistically significant reflex inhibition. This restoration of visually-mediated behaviour, observed in two independent groups, reveals that intraretinal grafts provide useful information to blinded hosts.

Acoustic Stimulation↗
PubMed2006

Activation and maturation of alloreactive CD4-independent, CD8 cytolytic T cells.

The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8+ T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8+ graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8+ T cells to the site of transplant, CD103 or CD69 expression on CD8+ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8+ T cells correlated with expression of CD25, CD154 and CD43 by CD8+ GICs, in vitro alloproliferation by recipient CD8+ T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8+ T cells into cytolytic effectors, which correlates with transplant rejection.

Animals↗
PubMed2000

Characterization of cytokine profiles in corneal allograft with anti-adhesion therapy.

BACKGROUND: The cytokine profiles of specific immunosuppression after anti-adhesion molecule therapy are unknown in a mouse corneal transplantation model. METHODS: Orthotopic mouse corneal transplantation was performed using BALB/c (H-2d) mice as recipients and C3H/He (H-2k) mice as donors. Anti-mouse very late antigen-4 and anti-mouse lymphocyte function-associated antigen-1 monoclonal antibodies (each at a dose of 0.25/mg/day) were administered i.p. until day 7. A second corneal transplantation was performed 5 weeks after the first grafting. Delayed hypersensitivity was tested after the second grafting. Corneal cytokine expression was examined immunohistochemically. The cytokine gene transcription level was assessed in the corneas and splenocytes. RESULTS: All allografts with anti-adhesion molecule therapy survived for 5 weeks. Two weeks after the second grafts in the fellow eye (7 weeks after the first grafts), 50% of the mice with successful grafts bilaterally had low delayed hypersensitivity responses. Low helper T 1 (interferon-gamma and interleukin-2) cytokine gene and protein expression in corneas was observed in monoclonal antibody-treated mice 3 weeks after the first grafting. The mice with successful second grafts showed low corneal T helper 1 cytokine gene and protein expression. High interleukin-4 gene transcription levels in corneas and splenocytes was obtained in both groups in which the grafts were accepted and rejected after the second grafts. CONCLUSIONS: The cytokine profile to differentiate alloantigen-specific acceptance with anti-adhesion therapy to lymphocyte function-associated antigen-1 and very late antigen-4 molecules from rejection after the second grafting is local and systemic low T helper 1 cytokine in corneal transplantation. High interleukin-4 cytokine expression in corneas and splenocytes is not associated with achievement of tolerance induction.

Animals↗
PubMed2006

Antiviral therapy for hepatitis C in the setting of liver transplantation.

Hepatitis C viremia after liver transplantation for hepatitis C virus (HCV) liver disease is universal. Progressive HCV disease after transplantation is the leading cause of death, graft failure, and retransplantation. Whether to treat, with which agents, and timing of therapy are unanswered questions. Timing options include pretransplantation, prophylactic, post-transplantation preemptive, and post-transplantation recurrence-based therapy. The latter is most commonly utilized. There are little data for each of these, much less comparisons. Pegylated interferon-alpha has supplanted standard interferon-alpha due to increased efficacy and is generally used in combination with ribavirin (RBV). Efficacy is less than in nontransplant settings due to immunosuppression, an increased prevalence of genotype 1 HCV, patient comorbidities, and decreased functional status. Administration of HCV therapy to cirrhotic patients prior to transplantation may eradicate or suppress HCV and prevent or reduce severity of recurrence. Sustained virological response (SVR) as high as 50% was attained in genotypes 2 or 3 HCV. Comparison of preemptive and histology-based post-transplantation HCV therapy should be done, and more data will be available on pretransplantation therapy. Post-transplant patients are less tolerant of therapy, particularly RBV. SVR, the primary goal of therapy, likely halts disease progression, but only 20% to 30% of treated patients achieve SVR. Preemptive therapy early after transplantation may have advantages due to the potential to delay or blunt severity of graft infection and recurrent hepatitis. In post-transplant therapy, RBV toxicity is attenuated in relation to decreased renal function, and side effects of interferon are more prominent. An ongoing trial will assess preemptive therapy with treatment after histologic recurrence. Novel anti-HCV therapies such as protease and polymerase inhibitors are emerging. These must be tested with urgency in the transplant setting. Retransplantation for progressive HCV disease is more controversial due to poor outcomes, graft shortage, and disease recurrence.

Journal Article↗
PubMed2006

[A case report of simultaneous liver, pancreas-duodenum, and kidney transplantation in a patient with post-hepatitic cirrhosis combined with uremia and insulin-dependent diabetes related to chronic pancreatitis].

OBJECTIVE: To study the effect of triple organ transplantation (liver, kidney, and pancreas) in patient of end-stage liver disease with renal failure and diabetes, and to explore the optimal surgical procedure. METHODS: Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation was performed on a 43-year-old male patient with exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) who developed hepatic and renal failure. The pancreatic exocrine secretions were drained enterically to the jejunum. Prednisone, tacrolimus, mycophenolate mofetil, and ATG were used as immunosuppression therapy. RESULTS: Good liver and pancreas allograft function recovery was achieved within 7 days after the operation. And the recovery of renal allograft function was delayed. The renal allograft was removed because of break-down of renal blood flow 16 days after the transplantation. A new renal transplantation was performed at the same position. The second kidney graft recovered its normal function 3 days later. Up to the writing of this paper no acute rejection of organs and such complications as pancreatitis, thrombosis, and localized infection occurred. The patient became insulin independent with normal liver and renal function. CONCLUSION: Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation can be a good method for the patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

Adult↗
PubMed2000

Role of the bladder in delayed failure of kidney transplants in boys with posterior urethral valves.

PURPOSE: There is a tendency toward less favorable long-term graft function in patients with posterior urethral valves than in controls. We studied the role of the bladder in boys who underwent transplantation by simultaneously evaluating renal graft and voiding function. MATERIALS AND METHODS: Between 1972 and 1994, 66 boys with posterior urethral valves underwent kidney transplantation. Of these boys 44 with a mean age of 9.7 years who retained a functional renal graft did not undergo any surgery on the lower urinary tract except for the initial treatment of posterior urethral valves. Long-term evaluation included a voiding questionnaire, radiological assessment and serum creatinine measurement. RESULTS: Average followup was 9.01 years (range 2.4 to 19.6). There was no voiding dysfunction symptomatology in 23 boys, while 3 (14.2%) and 8 (38.1%) of the remaining 21 had daytime and nighttime frequency, respectively. Dysuria and incontinence were present in 11 (52.4%) and 12 (57.1%) patients, respectively. Urodynamics in 11 cases revealed a mean bladder compliance plus or minus standard deviation of 11.3+/-2.8 ml./cm. water. In boys with a voiding disorder mean serum creatinine increased after 5 years of followup. At 10 years after kidney transplantation mean serum creatinine was 140.3+/-36.0 and 285.7+/-36.2 micromol./l. in asymptomatic boys and those with a voiding disorder, respectively (p<0.01). CONCLUSIONS: Valve bladder has a role in the deterioration of renal transplants in boys with posterior urethral valves. In those with a voiding disorder closer followup is needed, including urodynamic and radiological studies. Bladder dysfunction, such as hypocompliance and/or hyperreflexia, requires medical or surgical treatment.

Child↗
PubMedDate not supplied

Comparison of early postoperative function of liver and renal allografts with radionuclide imaging.

OBJECTIVES: Radionuclide imaging is a valuable tool during the early posttransplantation period for evaluating the functional status of renal and liver allografts. The aim of this study was to compare the early postoperative function of renal and liver allografts with serial radionuclide imaging. METHODS: Twenty-two renal and 22 liver allograft recipients were evaluated with serial radionuclide imaging. All grafts were from living related donors. For renal scintigraphy, recipients were injected with Tc-99m DTPA, and imaging was performed on postoperative days 3 and 7. Liver allograft recipients were evaluated with Tc-99m mebrofenin hepatobiliary scintigraphy within the first postoperative week and as required thereafter. The following parameters were computed for each scintigraphy: uptake, time to excretion of the radiopharmaceutical (T(ex)), and retention of radioactivity at the end of the study. RESULTS: Among 22 renal transplant recipients, 19 (86%) had normal uptake and T(ex) values on day 7 posttransplantation. Nine (41%) renal grafts exhibited retention. Among 22 liver transplant recipients, 7 (32%) had normal findings on the first hepatobiliary scan. All except eight liver grafts (64%) had a delay in T(ex), and 15 (68%) had parenchymal retention on the first scan, with improvement of function observed on serial scintigraphies obtained during follow-up. Decreases in uptake were seen less frequently and correlated with a prolonged postoperative hospital stay. CONCLUSION: Renal transplant recipients are more likely than liver allograft recipients to have a normal scintigraphy in the early posttransplantation period. Retention of radioactivity at the end of the study was the most frequently observed abnormality for both renal and liver allografts. Most liver transplant recipients exhibited a delay in excretion, and parenchymal retention, of radioactivity on the first evaluation, with subsequent improvement on follow-up serial scintigraphy studies.

Humans↗
PubMed2002

Assessment of the method and timing of repair of a brachial plexus traction injury in an animal model for obstetric brachial plexus palsy.

A Sunderland type IV traction injury to the C6 root of adult sheep or newborn lamb brachial plexus was used as a model for obstetric traction injury to the C5 root in humans. In one experimental cohort the injury was created and repaired using interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in a group of adult sheep and in a group of newborn lambs. In a second cohort a similar injury was created and repaired either immediately or after a delay of 30 days, using either interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in four groups of six newborn lambs. In all cases both functional and morphometric indices of nerve regeneration were poorer in the injured and repaired nerves than in normal nerves. In lambs the method of repair made no difference and no significant differences were found for any of the indices of nerve function or morphology. In sheep the use of muscle grafts was associated with a poorer outcome than the use of nerve autografts. Where a delay of 30 days had elapsed between injury and repair, the results using nerve autografts were not significantly different. Where freeze-thawed muscle autografts had been used, the maturation of the regenerated nerve fibres after delay was significantly poorer than after immediate repair. The electrophysiological variables CV(max) and jitter, which may be applied clinically, were found to be good discriminators of recovery in all of the animals and in respect of all procedures.

Analysis of Variance↗
PubMed1988

Arterial trauma in children: diagnosis and management.

Ninety-two children with arterial injuries were studied over a 14 year period, 66 boys and 26 girls, whose ages ranged from 14 months to 18 years. Thirty-eight children had associated nerve injuries and 21 had orthopedic injuries as well. Interval between initial evaluation and diagnosis of arterial injury ranged from immediate to six months--76% were treated within six hours of injury and 24% had a delay of greater than six hours before diagnosis. Arteriograms were performed on 20 (21%) of the children, and 13 of these were done late. Surgical treatment consisted of local debridement and end-to-end anastomosis, ligation, exploration with thrombectomy of distal branches, or bypass grafting with vein. Three children died in the immediate postoperative period, 83 had good functional results, and six had poor functional results. Four of these six had a delayed diagnosis of arterial injury, and had injuries in arteries adjacent to the elbow or knee. We conclude that early diagnosis of arterial injury and a more liberal use of arteriography is warranted in young trauma victims, especially in cases of fractures about the knee or elbow.

Adolescent↗
PubMed1991

Immunosuppressive effects of 2-acetyl-4-tetrahydroxybutyl imidazole (THI) in the rat.

THI is a component of ammonia caramel, a widely used food colouring. The effect of THI on the immune system has been determined in the male F344 rat. THI was given in the drinking water at doses of 1, 10 and 50 mg/l (equivalent to 0.1, 1 and 5 mg/kg per day) to animals on a vitamin B6-deficient diet. After 1 week, the immune competence of the animals was assessed under continued THI treatment. No marked changes in thymus or spleen weight were observed after THI treatment, although there was an increased number of pyknotic cells in the thymic cortex, mainly engulfed by macrophages and there appeared to be a slight thinning of the cortex area. THI produced a significant loss in T and B lymphocytes in peripheral blood but not in the spleen. No change in natural killer (NK) cell activity against YAC-1 target cells was observed in the spleen. The observed increase in NK cell activity in peripheral blood was due to an increase in circulating large granular lymphocytes (LGL). Although the serum antibody titre against keyhole limpet haemocyanin (KLH) was not affected by THI treatment, B cells showed less proliferation when cultured with lipopolysaccharide. T cell function was impeded as measured in mitogen-induced proliferation assay, delayed-type hypersensitivity assay and host versus graft (popliteal lymph node) assay. The results indicate that THI is an immunosuppressor in the rat, in whom it can produce profound lymphopenia and suppression of cell-mediated immunity.

Animals↗
PubMed2004

Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice.

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.

Animals↗