PubMed Health⌕ Search

Biomedical subjects

M Mohiuddin

Publications and source records attributed to M Mohiuddin.

At least 19 recordsLinked to original sources
PubMed1998

High-dose preoperative radiation and the challenge of sphincter-preservation surgery for cancer of the distal 2 cm of the rectum.

PURPOSE: Sphincter-preserving surgery for the management of distal rectal cancer is gaining recognition as an alternative to abdominoperineal resection and loss of anal function. The use of high-dose preoperative radiation appears to enhance the options for sphincter preservation, even in the most distal segments of the rectum. MATERIALS AND METHODS: Seventy patients with tumors located in the distal 2 cm of the rectum received a minimum dose of 40 to 45 Gy over 4 1/2 weeks at 1.8 to 2.5 Gy per fraction. Patients with unfavorable tumors were given an additional boost of 10 to 15 Gy. Surgery was performed 5 to 10 weeks following completion of radiation. Radical surgical resection was performed in 48 patients and full thickness local excision in 22. Follow-up ranged from a minimum of 1 year to a maximum of 10 years, with a median of 4 years. RESULTS: There was one perioperative mortality. Two patients did not have their colostomy closed because of complications. Late diversion was required in 4 patients, primarily for recurrent disease. Sixty patients (86%) maintained long-term satisfactory sphincter function. Local recurrence was observed in 9 patients (13%) and distant metastases in 12 patients (17%). The overall five-year actuarial survival rate was 82%. The 5-year survival and local recurrence for postradiation pathological stage of disease was: T0, T1, T2, N0--95% and 8%, T3, T4, N0--91% and 4%, T(any) N+--50% and 41%, respectively. CONCLUSION: High-dose preoperative radiation, in properly selected patients with rectal cancers of the distal 2 cm, offers opportunities for sphincter-preserving surgical resection with excellent local control, survival, and enhanced quality of life.

Adult↗
PubMed1998

Novel mutations in the polyadenine tract of the transforming growth factor beta type II receptor gene are found in a subpopulation of human pancreatic adenocarcinomas.

In this study, we determined the incidence of microsatellite instability (MIN) in pancreatic adenocarcinoma and determined whether MIN might target, for mutations, the simple nucleotide repeats of the transforming growth factor beta type II receptor (TGFBR2) gene. Forty-eight surgically resected pancreatic tumor tissue samples and two normal pancreas tissue samples were analyzed in this study. Microsatellite analysis was performed for six loci in 14 of the 48 tumor specimens for which we had matching normal genomic DNA. Only four of the 14 tumors (29%) were MIN-positive as determined by the presence of microsatellite variations in more than one locus. Interestingly, eight of the 14 specimens (57%) showed microsatellite variations or loss of heterozygosity at D18S34, suggesting that this locus may be a critical region of genetic instability in pancreatic tumorigenesis. Of the 48 tumors, only two (4%) showed mutations in the polyA region, one of the MIN-targeted sites of the TGFBR2 gene. DNA sequence analysis of these two specimens showed the presence of a two-base deletion in one tumor specimen and the other tumor specimen showed a base substitution in the polyA tract at codon 128 of the TGFBR2 gene. The fact that these mutations occurred in the polyA tract of some pancreatic tumors suggests that a subpopulation of these tumors may be susceptible to MIN-targeted mutations. The incidence of these mutations are low and similar to that reported for nonhereditary, sporadic colon cancers.

Adenocarcinoma↗
PubMed1998

Radical Sphincter preservation surgery with coloanal anastomosis following high-dose external irradiation for the very low lying rectal cancer.

High-dose preoperative radiation and specifically designed surgical techniques were used to extend the application of sphincter preservation surgery for cancer of the distal 3 cm of the true rectum. A total of 203 consecutive patients with rectal cancer were treated with external-beam irradiation (45-70 Gy) and radical curative surgery. The cancer was at the level of 0.5-3.0 cm in 65 patients. In these 65 patients treated by radical resection with coloanal anastomosis six suffered recurrence (9%), and the 5-year actuarial survival was 85%. There was a single death. There was no local recurrence among 44 patients in whom the postradiated cancer resided in the rectal wall with or without nodal involvement. With proper selection, high-dose preoperative radiation therapy thus permits extended use of sphincter preservation surgery with coloanal anastomosis for cancers of the distal 3 cm of the true rectum.

Adult↗
PubMed1997

Ionizing radiation-inducible apoptosis in the absence of p53 linked to transcription factor EGR-1.

The tumor suppressor protein p53 is a pivotal regulator of apoptosis, and prostate cancer cells that lack p53 protein are moderately resistant to apoptotic death by ionizing radiation. Genes encoding the transcription factor early growth response-1 (EGR-1) and cytokine tumor necrosis factor-alpha (TNF-alpha) were induced upon irradiation of prostate cancer cells, and inhibition of EGR-1 function resulted in abrogation of both TNF-alpha induction and apoptosis. Induction of the TNF-alpha gene by ionizing radiation and EGR-1 was mediated via a GC-rich EGR-1-binding motif in the TNF-alpha promoter. Because TNF-alpha induces apoptosis in prostate cancer cells, these findings suggest that, in the absence of p53, ionizing radiation-inducible apoptosis is mediated by EGR-1 via TNF-alpha transactivation.

Apoptosis↗
PubMed1997

Role of O6-methylguanine-DNA methyltransferase in the resistance of pancreatic tumors to DNA alkylating agents.

Pancreatic adenocarcinomas rarely respond to radiation or chemotherapy, indicating that a large percentage of these tumors possess complex mechanisms of resistance. The failure of alkylating agents, such as carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea; BCNU], lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CCNU], and streptozotocin, to yield consistent therapeutic results further suggests that one of these mechanisms may be the high expression of O6-methylguanine-DNA methyltransferase (MGMT). All 12 human pancreatic ductal adenocarcinomas assayed for MGMT activity showed unusually high levels, implying that these malignancies are efficient in repairing genotoxic O6-alkylguanine lesions induced by methylating (streptozotocin) and 2-chloroethylating (BCNU and CCNU) chemotherapeutic genotoxic agents. Immunohistochemical analysis of an additional 15 pancreatic tumors showed that high levels of MGMT protein reside in the nucleus and the cytoplasm of malignant cells. Both nuclear and cytoplasmic staining were absent in hyperplastic duct epithelium, but staining was invariably present in moderate to highly dysplastic foci and especially strong in invasive components of the tumor. With the exception of lymphocytes that were MGMT positive, acinar, ductal, and islet cells did not stain for MGMT in histologically normal pancreata. These data indicate that MGMT activity is up-regulated in dysplastic epithelium, and its expression increases during tumor progression, reaching the highest levels in the invasive components of the tumor. Resistance of pancreatic tumor cells to alkylating agents was verified with four pancreatic tumor cell lines. CAPAN-2, CFPAC-1, PANC-1, and MIAPaCa-2, having MGMT levels of 1800, 987, 700, and 880 fmol/mg protein, respectively, were resistant to BCNU, but their resistance declined sharply following pretreatment with the MGMT inhibitor O6-benzylguanine (O6-BG). On the other hand, PANC-1 and MIAPaCa-2 could not be eradicated with N-methylnitrosourea (MNU) at concentrations as high as 2 mM, even when pretreated with O6-BG. These two lines were shown to be modified genetically in microsatellite sequences by MNU and are believed to have a defective mismatch repair system, which may explain their resistance to methylating agents. Failure of pancreatic tumors to respond to nitrosoureas is related to high levels of MGMT expression and in some cases to genomic instability. However, these tumors can be sensitized to chloroethylating drugs and eradicated following the elimination of MGMT activity by O6-BG or homologous MGMT inhibitors.

Adenocarcinoma↗
PubMed1997

Curative surgical resection following reirradiation for recurrent rectal cancer.

PURPOSE: In spite of adjunctive radiation and chemotherapy, 10 to 25% of patients with resected rectal cancer develop local recurrence in the pelvis. This study evaluates the potential for curative surgical resection of residual disease following reirradiation for recurrent rectal cancer. METHODS AND MATERIALS: Thirty-nine patients with recurrent adenocarcinoma of the rectum following prior adjunctive therapy underwent reirradiation of the pelvis with concurrent intravenous infusion of 5-fluorouracil. Median time to recurrence following initial treatment was 18 months. Prior radiation doses to the pelvis ranged from 40 to 66 Gy with a median of 50.4 Gy. Reirradiation doses ranged from 20 Gy to 49.2 Gy with a median total dose of 36 Gy. Eight to 12 weeks following reirradiation patients underwent surgical resection of disease. Thirty-one patients had gross total resection of tumor. RESULTS: Patients have been followed for 24 months to 75 months after reirradiation for recurrent rectal cancer with a median follow-up of 3 years. Reirradiation was well tolerated, with seven patients requiring a significant treatment break. Early termination of reirradiation occurred in five patients because of diarrhea, moist desquamation, or mucositis. No surgical mortality was observed. Postoperatively, two patients developed delayed wound healing. Late complications included six patients who developed small bowel obstruction with three patients developing a bowel fistula. The median survival of patients is 45 months, with a 5-year actuarial survival of 24%. Actuarial local control at 5 years was 45%. The rate of distant metastases was 17%. CONCLUSION: Selected patients with rectal cancer who develop recurrent disease following previous adjuvant therapy can undergo successful curative surgical resection following reirradiation/chemotherapy with significant long-term survival.

Adenocarcinoma↗
PubMed1997

Efficacy of postoperative radiation therapy for recurrent squamous cell carcinoma of the head and neck.

PURPOSE: Postoperative radiation therapy (RT) following surgical resection is often the recommended treatment for recurrent squamous cell carcinoma (SCC) of the head and neck. Despite common use, there are few published series evaluating such a management approach. METHODS AND MATERIALS: We evaluated the efficacy of postoperative RT in 31 patients with recurrent SCC of the head and neck treated between 1981 and 1993. None of the patients had prior RT. All had complete resection of recurrent gross disease and no distant metastases. Maximum postoperative RT doses ranged from 59.4-70 Gy (median = 66 Gy). RESULTS: The 5-year disease-specific survival (DSS) and local control (LC) rate for all patients were 32 and 46%, respectively. Several prognostic factors were analyzed including site and stage of original primary tumor, disease-free interval, site of recurrence, status of surgical margins, and dose. Only site of recurrence significantly influenced both DSS and LC. Patients whose recurrence was limited to previously undissected tissue had 5-year DSS and local control rates of 60 and 74%, respectively, as compared to 19 and 29%, respectively, for patients whose recurrence was within previously dissected tissue (p = 0.05). CONCLUSIONS: Patients with recurrent SCC of the head and neck treated with standard postoperative RT following surgical resection do relatively well if the recurrence is within previously undissected tissue (i.e., nodal only); however, patients whose recurrence is within previously dissected tissue do poorly. Every effort to prevent locoregional disease recurrence at the time of primary therapy should be emphasized.

Adult↗
PubMed1997

Palliative reirradiation for recurrent rectal cancer.

PURPOSE: The purpose of this study was to analyze the efficacy and acute and late toxicity of reirradiation for recurrent rectal cancer. METHODS AND MATERIALS: Fifty-two patients with recurrent rectal adenocarcinoma following previous pelvic RT underwent reirradiation. Median initial RT dose to the pelvis was 50.4 Gy. Median reirradiation dose was 30.6 Gy. Twenty-two patients received 1.2 Gy b.i.d., and 30 patients received 1.8-2.0 Gy daily. Total cumulative doses ranged from 66.6 to 104.9 Gy (median: 84.4 Gy). Forty-seven patients (90%) received concurrent 5-FU chemotherapy. Forty-four patients were followed until death, and the median follow-up time was 16 months. RESULTS: The RTOG Grade 3 acute toxicity rate was 31%. The RTOG Grade 3 and 4 late toxicity rates were 23 and 10%, respectively. On multivariate analysis, the only factor associated with reduced late toxicity was hyperfractionated delivery of reirradiation. Bleeding, pain, and mass effect were palliated completely in 100, 65, and 24% of instances, respectively, and the majority of responding patients were palliated until death. The overall median survival time from retreatment was 12 months. The 2- and 3-year overall actuarial survival rates were 25 and 14%, respectively. CONCLUSION: This unique institutional approach to recurrent rectal cancers resulted in excellent palliation of symptoms. Late complications appeared reduced by hyperfractionated treatment delivery.

Adult↗
PubMed1997

Differential dose delivery using a nondocking applicator for intraoperative radiation therapy.

PURPOSE: Although treatment of a field within a field to deliver a boost dose is quite common with external photon beam radiation therapy, the same is not always true with electron beam radiation or in intraoperative radiation therapy (IORT). The purpose of this work is to report the results and details of a new technique developed to treat a field within a field in intraoperative radiation therapy. METHODS AND MATERIALS: This technique makes use of the nondocking IORT system currently used at our institution. Treatment is given in two segments: the large field is first treated by using standard circular lucite cones; the second dose segment is delivered using a new circular brass cone designed to fit concentrically within the large lucite cone. RESULTS: Central axis depth dose, surface dose, output factors, and two-dimensional beam profiles have been measured for a 7 cm inner diameter (i.d.) flat lucite cone and 3.8 and 5 cm i.d. flat brass cones for electron beam energies ranging from 4-22 MeV. For different clinical target volumes, summed dose distributions differentially weighted in both energy and dose are presented. CONCLUSIONS: A simple technique for delivering differential dose in intraoperative radiation therapy is presented. The technique provides a method for escalating dose to higher values for a defined target volume.

Equipment Design↗
PubMed1997

Current and emerging treatments for pancreatic cancer.

The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil. Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.

Antimetabolites, Antineoplastic↗
PubMed1997

Critical issues in the evolving management of rectal cancer.

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.

Combined Modality Therapy↗
PubMed1996

Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats.

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.

Acute Disease↗
PubMed1996

EGR-1 induction is required for maximal radiosensitivity in A375-C6 melanoma cells.

Exposure to ionizing radiation leads to induction of the immediate-early gene, early growth response-1 (Egr-1). Previous studies have suggested distinct cell type- and inducer-specific roles for EGR-1 protein in cellular growth inhibition. The present study was undertaken to determine the functional role of EGR-1 in growth inhibition caused by exposure of tumor cells to ionizing radiation. Exposure to ionizing radiation caused induction of EGR-1 protein in human melanoma cells A375-C6. Inhibition of either the function of EGR-1 protein by stable transfection with a dominant-negative mutant or the expression of EGR-1 by transient transfection with an antisense oligomer resulted in a diminished growth-inhibitory response to ionizing radiation. Because previous studies have suggested that mutations in the tumor-suppressor gene p53 confer radio-resistance, we examined the p53 status of A375-C6 cells. Interestingly, both the parental and the transfected A375-C6 cells showed trisomy for wild-type p53 alleles. Exposure to ionizing radiation resulted in induction of p53 protein that localized to the nucleus in A375-C6 cells. These data suggest that inhibition of EGR-1 function confers radio resistance despite the induction of wild-type nuclear p53. Thus, EGR-1 is required for the growth-inhibitory response to ionizing radiation in A375-C6 cells.

Cell Division↗
PubMed1996

Prognostic significance of tumor fixation of rectal carcinoma. Implications for adjunctive radiation therapy.

BACKGROUND: This study was conducted to assess the prognostic significance of adjunctive radiation in the surgical management of rectal carcinoma patients with tumor fixation. METHODS: Two hundred and ninety-seven patients with a histologic diagnosis of adenocarcinoma of the rectum were treated with high dose preoperative radiation ( > or = 45 Gray [Gy]) followed by surgical resection of the tumor (Group A). One hundred and seventy-four patients underwent initial curative surgery (Group B) followed by selective postoperative radiation (45-50 Gy) for those with pathologic T3, T4, or N+ (B2, C) cancers (N = 143). The two patient groups were compared by presenting clinical stage of the disease to assess the prognostic significance of tumor fixation on results of adjunctive therapy. Follow-up ranged from 24 months to 180 months. RESULTS: The 5-year actuarial survival of Groups A and B was similar, 69% and 61% respectively. Survival was significantly better for Group A patients with fixed cancer (57% vs. 33%, P = 0.003). Survival was also better for patients in Group A with tumors located in the distal rectum (70% vs. 56%, P = 0.02). The local recurrence rate for patients with tumors located in the distal rectum was 17% for Group A and 19% for Group B (P = 0.74). The local recurrence rate for fixed cancers was 23% and 50% for Group A and Group B respectively (P = 0.0009). The incidence of small bowel complications (Grade 3 or 4) was lower for patients undergoing preoperative radiation compared with patients treated with postoperative radiation, (4% vs. 13%, P < 0.05). CONCLUSIONS: When special considerations of sphincter-preserving surgery are not an issue, mobile rectal carcinoma may be effectively treated with surgery and selective postoperative radiation. However, fixed tumors, especially those located in the distal rectum, are better treated with high dose preoperative radiation.

Adenocarcinoma↗
PubMed1996

Expression and mutation of H-ras in uterine cervical cancer.

In cervical cancer, abnormalities of ras genes have not been fully investigated. We studied the expression and mutation of H-ras oncogene in cervical cancer to investigate their relationship and usefulness as an independent prognostic indicator. Twenty-seven paraffin-embedded resection specimens of cervical cancer (21 squamous, 3 adeno, 2 adenosquamous, and 1 small cell) were examined by immunohistochemistry using a mAb H-ras p21 and by PCR and allele-specific oligonucleotide hybridization using H-ras codon 12 and 61 amplimers and oligonucleotide probes. A strong immunoreaction was noted in 10 cases (37%) and weak immunoreaction in an additional 6 cases (22%). H-ras codon 12 mutations were detected in 6 of 27 cases (22%) and all of the mutations were guanine to adenine transitions. There was no mutation in codon 61. Cases with codon 12 mutations included all 3 squamous, 2 adeno, and I adenosquamous carcinoma. Only 3 of 16 (19%) cases with positive staining and 3 of 11 (27%) cases with negative staining showed mutations. No correlation was found between ras gene alterations and patient survival time. Our findings indicate that expression and mutation of H-ras oncogene occur in cervical cancer but their determination adds no useful prognostic information.

Adult↗
PubMed1996

Tolerance to cardiac allografts requires a time lag between intrathymic treatment and transplantation.

Permanent tolerance to an experimental heterotopic cardiac allograft can be achieved by pretreatment with antilymphocyte serum (ALS) and intrathymic inoculation of donor cells. Most successful experimental protocols have employed a time lag of 2 to 3 weeks between intrathymic pretreatment and transplantation, which makes this treatment strategy impractical for clinical heart transplantation. In these experiments we modified the standard protocol by giving ALS 24 hr prior to both intrathymic injection of donor cells and heterotopic transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS and 24 hr later underwent intrathymic injection of 5 X 10(7) donor Lewis-Brown Norway (LBN) splenocytes and heterotopic cardiac transplantation using an LBN donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day graft survival observed in untreated Lewis recipients (n = 5) (P < 0.02). However, graft survival was not different from that observed in Lewis rats pretreated with ALS alone (n = 5) (25.8 days, P = NS). Permanent graft survival was produced in two rats receiving only A-LS and in one rat receiving both ALS and intrathymic inoculation. In these experiments it appears that prolongation of graft survival may have been due to the effect of A-LS alone. These results suggest that there is a critical time period between intrathymic inoculation and transplantation that is needed for permanent tolerance to be induced consistently. This may be due to the kinetics of the effects of ALS on alloreactive T-lymphocytes or to a time-dependent requirement for antigen processing in the thymus.

Animals↗
PubMed1996

Fetal inoculation with donor cells in cardiac xenotransplantation.

BACKGROUND: In utero fetal inoculation with allogeneic cells has produced subsequent tolerance to experimental cardiac allografts. We attempted to extend this observation to a model of xenogeneic cardiac transplantation. METHODS: Lewis rat fetuses were inoculated with Golden Syrian hamster thymocytes (n = 5) or whole spleen cells (n = 5) on the tenth day of intrauterine life. Six weeks after the birth of pretreated fetuses, heterotopic cardiac transplantation using a hamster donor was performed. Three to 4 weeks after parturition, we performed heterotopic cardiac transplantation using hamster donors in the female Lewis rats whose fetuses had been treated in utero. RESULTS: Animals treated in utero with either thymocytes or whole spleen cells had graft survival of 3 days, not different from that in untreated Lewis rats (n = 5) (p = not significant). Maternal Lewis rats whose fetuses were treated with thymocytes (n = 5) or whole spleen cells (in = 4) had markedly reduced survival of xenogeneic cardiac grafts (range, 3 to 20 hours; mean, 15 hours; p < 0.01; and range, 5 to 15 minutes; mean, 10 minutes; p < 0.01, respectively). Female Lewis rats without intrauterine inoculation (n = 5) had expected xenograft survival time (3 days) (p = not significant). Immunohistochemical staining of hyperacutely rejected grafts showed deposits of immunoglobulin M as well as immunoglobulin G and complement. In normally rejected xenografts, no immunoglobulin M was detected. CONCLUSIONS: These studies reveal the surprising observation that fetal exposure to xenogeneic cells sensitizes the maternal rat without tolerizing the fetal rat as observed in an allograft model. In addition, whole spleen cells produce a more vigorous hyperacute rejection than thymocytes, suggesting that B cells or macrophages may be the sensitizing agents. The accelerated rejection observed has the characteristics of an immunoglobulin M antibody-mediated hyperacute rejection response with deposition of complement.

Animals↗