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Unlabelled: Early corticosteroid withdrawal has recently been shown to be possible in recipients of simultaneous pancreas kidney transplants; however, its feasibility in solitary pancreas recipients has not been documented. In the present study, we provide evidence that early withdrawal can be achieved in pancreas as well as pancreas-kidney recipients., Methods: Twenty type I diabetics underwent 13 pancreas-kidney transplants and 7 pancreas-only transplants with early withdrawal (methylprednisone 6-day taper). Additional immunosuppression consisted of tacrolimus, mycophenolate mofetil, and thymoglobulin induction (five doses)., Results: Transplants included 13 pancreas-kidney, 6 pancreas after kidney transplant, and 1 pancreas after islet transplant. Overall mean follow-up was 7.3 months. One episode of pancreas transplant rejection after pancreas-only transplant was detected on protocol biopsy without biochemical abnormalities. One renal allograft rejection occurred 65 days posttransplant in a pancreas-kidney recipient and was graded as a Banff IA rejection. A single pancreas graft loss occurred due to thrombosis 6 days after pancreas-kidney transplantation., Conclusions: These results indicate that relatively short thymoglobulin induction (five doses) with tacrolimus and mycophenolate mofetil can allow early withdrawal in both pancreas-kidney and pancreas-only transplant recipients.

Unlabelled: The purpose of this study was to evaluate the clinical impact of methicillin-resistant Staphylococcus aureus (MRSA) infections on transplant recipients., Methods: Liver and kidney recipients with MRSA infections were retrospectively identified and compared to an age, gender, UNOS status, organ transplanted, and transplant date matched (2:1) non-MRSA-infected recipient control group. All MRSA infections were initially treated with vancomycin, and four (33%) liver recipients were converted to linezolid therapy after failing to improve with vancomycin., Results: The overall MRSA infection incidence was 1.4% (24/1770) with MRSA more common in liver (3.75%; 12/320) than kidney transplants (0.8%; 12/1450) (P < .001). The most common sites of MRSA infection were blood (42%), lung (38%), and abdomen (29%). The MRSA group had a greater percentage of prior antibiotic usage (79% vs 40%; P < .0015). The MRSA group experienced more posttransplant complications (52% vs 19%; P < .011)), and exhibited a trend toward greater length of stay in the intensive care unit (7.8 vs 4.6 days; P = .09), but not overall length of stay. Survival was similar in MRSA and non-MRSA groups (75% vs 88%; P = .17). No significant differences in mortality were noted between liver and kidney recipients infected with MRSA (P = .6)., Conclusion: MRSA infection is associated with a higher incidence of posttransplant complications and antibiotic usage in both liver and kidney recipients compared to patients with MRSA infection.

The shortage of liver donors and the increasing number of patients on the waiting list for liver transplantation have led to a widening of the definition of suitable liver donors. In this case report, we describe transplantation of a liver from a 20-year-old brain-dead donor with a past history of schistosomiasis. Careful evaluation for schistosomiasis-related hepatic complications using hepatic function tests, clinical assessment for manifestations of portal hypertension, as well as abdominal ultrasound, and liver biopsy were performed. At 7 months follow-up, the recipient is doing well with normal liver function. Liver transplantation from a donor with a history of schistosomiasis is acceptable in carefully screened cases.

Background: Venous thrombosis remains an important cause of pancreatic graft loss. Nevertheless, reports are scarce of treatment alternatives to complete graft removal. We describe a case of surgical salvage of a partial pancreatic graft thrombosis., Methods: We used descriptive retrospective analysis., Results: A 36-year-old patient with juvenile-onset diabetes mellitus and previous living related renal transplant received a cadaveric pancreas transplant in the right iliac fossa with enteric exocrine drainage and standard vascular anastomosis. Two days after discharge from the hospital, he presented with severe right upper quadrant pain, nausea, vomiting, fever, and leukocytosis. He was taken to the operating room for exploration. The tail of the pancreas, which was kinked under the gallbladder, was necrotic and excised. The remainder of the pancreas looked normal. The patient recovered well from surgery and was discharged home 7 days later., Conclusions: Partial pancreatectomy is an acceptable surgical alternative for incomplete graft thrombosis.

Background: Numerous factors are known to impact on patient survival after renal transplantation. Recent studies have confirmed a survival advantage for renal transplant patients over those waiting on dialysis. We aimed to investigate the hypothesis that longer waiting times are more deleterious than shorter waiting times, that is, to detect a "dose effect" for waiting time., Methods: We analyzed 73,103 primary adult renal transplants registered at the United States Renal Data System Registry from 1988 to 1997 for the primary endpoints of death with functioning graft and death-censored graft failure by Cox proportional hazard models. All models were corrected for donor and recipient demographics and other factors known to affect outcome after kidney transplantation., Results: A longer waiting time on dialysis is a significant risk factor for death-censored graft survival and patient death with functioning graft after renal transplantation (P < 0.001 each). Relative to preemptive transplants, waiting times of 6 to 12 months, 12 to 24 months, 24 to 36, 36 to 48, and over 48 months confer a 21, 28, 41, 53, and 72% increase in mortality risk after transplantation, respectively. Relative to preemptive transplants, waiting times of 0 to 6 months, 6 to 12 months, 12 to 24 months, and over 24 months confer a 17, 37, 55, and 68% increase in risk for death-censored graft loss after transplantation, respectively., Conclusions: Longer waiting times on dialysis negatively impact on post-transplant graft and patient survival. These data strongly support the hypothesis that patients who reach end-stage renal disease should receive a renal transplant as early as possible in order to enhance their chances of long-term survival.

Background: Anemia is a significant problem in many disease states. Erythropoietin (Epo) has been used in the treatment of anemia associated with numerous chronic diseases. This study investigates the dose-response profiles of a single intramuscular (im) injection of a recombinant adeno-associated virus vector (rAAV) containing the Epo gene with the goal of achieving a sustained elevation of hematocrit (Hct)., Methods: Cynomolgus (cm) monkeys were given single injections of different doses of rAAV-cm-Epo. The biological effect of Epo gene expression was monitored by determining the Hct levels and circulating hormone levels by ELISA. Antibody to the rAAV capsid protein was also measured over the 41-week period of the experiment., Results: Epo expression was noted only when 2 x 10(11) or more particles were injected. Epo was noted to be increased as soon as 1 week postinjection and was maximum in 6 to 8 weeks. This level of expression remained constant for nearly 20 weeks. Animals given the highest dose of rAAV developed a higher Hct over the first 8 weeks postinjection than those given an intermediate dose. However, the maximum levels of hemoglobin were the same. There was a weak correlation between amount of rAAV injected and capsid antibody response., Conclusions: AAV vectors are able to transduce skeletal muscle and are capable of achieving sustained expression and systemic delivery of a therapeutic protein following a single im administration. Dose responses to rAAV-Epo are achievable, although a threshold inoculum of virus is necessary to produce an effect and the therapeutic window is narrow., (Copyright 2000 Academic Press.)

Background: There are presently no established pre-transplant tests that consistently identify patients who may be at increased risk for acute rejection episodes after renal transplantation. We studied whether pretransplant serum levels of C-reactive protein (CRP), a marker for the presence of systemic inflammation, would predict the occurrence of acute rejection episodes after renal transplantation., Methods: Pretransplant serum was tested for CRP level in 97 consecutive renal transplant recipients. Time to acute rejection after transplantation was stratified by CRP level and compared using the Kaplan-Meier method. In addition, Cox regression multivariate analysis was performed to assess whether any pretransplant covariates could independently predict the subsequent occurrence of acute rejection episodes., Results: Pretransplant mean CRP levels were higher in patients who subsequently had a rejection episode versus those who had no rejection (22.2+/-2.9 vs. 11.7+/-1.8 microg/ml, respectively, P=0.003). Patients less than the median CRP value had a significantly longer time to rejection compared to those with higher CRP levels (P=0.002). Similarly, patients within the lowest CRP quartile had longer times to rejection when compared with the highest quartile (P=0.006). Cox proportional hazards regression multivariate analysis identified CRP level as the only independent pretransplant risk factor for rejection identified (P=0.044)., Conclusions: Pretransplant systemic inflammation as manifested by elevated serum CRP level independently predicts the risk of acute rejection after renal transplantation and may be useful in stratifying patients at the time of transplantation according to immunological risk. Thus, assessment of pretransplant systemic inflammatory status may be helpful in prospective individualization of immunosuppression therapy after renal transplantation.

Objective: To evaluate whether intravascular volume expansion would improve renal blood flow and function during prolonged CO2 pneumoperitoneum., Summary Background Data: Although laparoscopic living donor nephrectomies have a considerably reduced risk of complications for the donors, significant concerns exist regarding procurement of a kidney in the altered physiologic environment of CO2 pneumoperitoneum. Recent studies have documented adverse effects of CO2 pneumoperitoneum on renal hemodynamics., Methods: Renal and systemic hemodynamics and renal histology were studied in a porcine CO2 pneumoperitoneum model. After placement of a pulmonary artery catheter, carotid arterial line, Foley catheter, and renal artery ultrasonic flow probe, CO2 pneumoperitoneum (15 mmHg) was maintained for 4 hours. Pigs were randomized into three intravascular fluid protocol groups: euvolemic (3 mLkg/hour isotonic crystalloid), hypervolemic (15 mL/kg/hour isotonic crystalloid), or hypertonic (3 mL/kg/hour isotonic crystalloid plus 1.2 mL/kg/hour 7.5% NaCl)., Results: In the euvolemic group, prolonged CO2 pneumoperitoneum caused decreased renal blood flow, oliguria, and impaired creatinine clearance. Both isotonic and hypertonic volume expansions reversed the changes in renal blood flow and urine output, but impaired creatinine clearance persisted., Conclusions: Intravascular volume expansion alleviates the effects of CO2 pneumoperitoneum on renal hemodynamics in a porcine model. Hypertonic saline (7.5% NaCl) solution may maximize renal blood flow in prolonged pneumoperitoneum, but it does not completely prevent renal dysfunction in this setting. This study suggests that routine intraoperative volume expansion is important during laparoscopic live donor nephrectomy.

Objective: Primary biliary cirrhosis (PBC) is an autoimmune disease affecting small intrahepatic bile ducts of the liver, causing destruction of the epithelium that results in eventual fibrosis and scarring. We still lack a complete epidemiological description of this disease, although interesting geographic differences in prevalence have been described. One consistent feature has been the relative scarcity of men with PBC. In fact, published ratios of women to men range from 3:1 to as high as 22:1. Thus far, the only clinical difference reported between men and women with PBC is a putative higher risk of hepatocarcinoma in men. Previous serological studies have shown that about 95% of all patients possess antimitochondrial antibodies to members of the highly conserved 2-oxo-acid dehydrogenase family of proteins, namely pyruvate dehydrogenase complex E2 (PDC-E2), branched-chain 2-oxo-acid dehydrogenase complex E2 (BCOADC-E2), and 2-oxo glutarate dehydrogenase complex E2 (OGDC-E2). However, there has been no information as to whether there is a difference in serological response between men and women. Using the serological hallmark of antimitochondrial antibodies (AMAs) and taking advantage of the availability of recombinant mitochondrial autoantigens, investigations were performed to determine if there were any serological differences between men and women with PBC., Methods: Sera were collected from 88 patients with PBC, of whom 46 were men and 42 were women. Using a combination of immunoblotting and enzyme-linked immunoabsorbent assay (ELISA) against beef heart mitochondria (BHM), recombinant PDC-E2, BCOADC-E2, and OGDC-E2, we determined the relative autoantibody reactivities of our study population., Results: Both men and women with PBC produced high titer antimitochondrial antibodies. The frequency of reactivity was similar in both groups and included, in descending order, PDC-E2, E3BP (Protein X), BCOADC-E2, and finally OGDC-E2. More importantly, antigenic specificity was nearly identical regardless of gender., Conclusions: AMAs are the serological hallmark of PBC in both men and women, and there is no significant difference in reactivity between the two groups of patients.

Hepatic artery thrombosis remains one of the most serious complications after orthotopic liver transplantation. Sepsis, biliary leakage and strictures, and retransplantation are often the result of this devastating complication. Because retransplantation or reoperation is sometimes not possible or advisable, other means of reestablishing hepatic artery continuity are desirable. We describe a liver transplant recipient who developed a dissection of an iliac artery conduit after retransplantation that was treated with fibrinolytic therapy followed by successful placement of an endovascular stent.

The Michigan Kidney Transplant Program has existed for 35 years. Outcomes have improved dramatically as the one-year survival of cadaver kidney grafts increased from 25% to 85-90%. Patient deaths in the first year are now uncommon. Indications for renal transplantation have been extended to infants, the elderly, diabetics and to patients with other significant health problems who would not have been candidates in the past. Chronic administration of large doses of corticosteroids is no longer necessary and the associated morbidity is largely avoided. Improvements in immunosuppression, especially the introduction of cyclosporine, account for much of this progress. With success has come increasing demand. Unfortunately, the gap between the number of available donor kidneys and the number of patients listed for a cadaver transplant continues to increase rather than diminish. Greater acceptance of volunteer donation, as has occurred in our own program, will help to reduce this shortage. If the past forecasts the future, we can anticipate extraordinary advances during the next 35 years.

Background: Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2) has been shown to be a mechanism of the immunosuppressive effect of portal venous transfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has received increased attention because of its ability to enhance gene transcription. This study tested the hypothesis that the intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production and thus augments the immunosuppressive effect of PVT., Methods: Butyrate was incorporated into liposomes and administered intravenously to Lewis rats. Control rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml of Wistar-Furth blood. Kupffer cells were isolated, and PGE2 and tumor necrosis factor-alpha levels were measured in the culture medium after 24 hr. Additionally, Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures., Results: Intrahepatic delivery of butyrate via liposomes increased Kupffer cell PGE2 (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupffer cell-mediated immunosuppression as demonstrated by significant depression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm, P<0.01)., Conclusion: The results support the hypothesis that intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production, and specific targeting of Kupffer cells with liposomes containing immunomodulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.

Background: The number of patients waiting lung transplantation greatly exceeds the supply of donors. This study was conducted to determine the effect of high-dose steroid administration on oxygenation and donor lung recovery after brain death., Methods: A retrospective analysis was conducted on 118 consecutive organ donors from January 1 through December 31, 1995. Eighty donors received high-dose steroids (methylprednisolone, mean 14.5+/-0.06 mg/kg) after organ procurement organization management began; a second group was composed of 38 patients who received no steroids. PaO2/FiO2 ratios were used to evaluate oxygenation. The number of single and double lungs transplanted served as the endpoint., Results: No differences were noted in hemodynamics, most clinical or demographic variables and initial values of PaO2/FiO2 between groups. However, nonsteroid-treated donors showed an overall decrease in oxygenation (mean decrease in PaO2/FiO2 -34.2+/-14), whereas steroid-treated donors had a significant and progressive increase in oxygenation (mean increase in PaO2/FiO2: 16+/-14) before aortic cross-clamping (p = 0.01). Time before cross-clamping was longer in the steroid-treated patients (p = 0.003). The number of procured lungs was markedly greater in steroid-treated than nonsteroid-treated donors (25/80 patients vs 3/38; p < 0.01)., Conclusions: High-dose methylprednisolone given during donor management results in improved oxygenation at organ recovery. This treatment resulted in a significant increase in the number of lungs transplanted and may have enabled donors to be treated longer.

A 55-year-old woman developed end-stage liver disease and the hepatorenal syndrome secondary to cryptogenic cirrhosis. Orthotopic liver transplantation was complicated by bile peritonitis, requiring reoperation and eventual placement of an internal biliary stent. On postoperative day 26, hemobilia was caused by localized rupture of mycotic (Aspergillus fumigatus) hepatic artery pseudoaneurysms with fistulization into the biliary tree. After arterial reconstruction with a reversed autologous saphenous vein graft, the patient was treated successfully with liposomal amphotericin B.

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.

Objective: The authors analyze a single center's 11-year experience with 190 orthotopic liver transplants for congenital biliary atresia., Summary Background Data: Hepatic portoenterostomy generally is the initial treatment for children with congenital biliary atresia. Despite multiple modifications of the hepatic portoenterostomy, two thirds of treated patients still develop recurrent cholestasis, portal hypertension, cholangitis, and cirrhosis. Therefore, the only hope of long-term survival in the majority of children with congenital biliary atresia is definitive correction with orthotopic liver transplantation., Methods: The medical records of 190 consecutive patients undergoing orthotopic liver transplantation for congenital biliary atresia from July 1, 1984 to February 29, 1996 were reviewed. Results were analyzed via Cox multivariate regression analysis to determine the statistical strength of independent associations between pretransplant covariates and patient and graft survival. Actuarial patient and graft survival was determined at 1, 2, and 5 years. The type and incidence of post-transplant complications were determined, as was the quality of long-term graft function. The median follow-up period was 3.21 years., Results: The liver grafts were comprised on 155 whole-organ, 24 reduced-size, and 11 living donor organs. Median pretransplant values for recipient age, weight, and total bilirubin were 1.4 years, 12.3 kg, and 13.8 mg/dL, respectively. One hundred sixty-four patients (86%) had undergone prior hepatic portoenterostomy. Eighty-seven patients (46%) were United Network for Organ Sharing (UNOS) status 1 or 2 at the time of liver transplantation. The majority (15/24, 62%) of reduced-size graft recipients were UNOS status I at the time of transplantation. One hundred fifty-nine patients (84%) received a single graft, whereas 31 patients required 37 retransplants. The 1, 2, and 5 year actuarial patient survival rates were 83%, 80% and 78% respectively, whereas graft survival rates were 81%, 77%, and 76%, respectively. Cox multivariate regression analysis demonstrated that pretransplant total bilirubin, UNOS status, and graft type significantly predicted patient survival, whereas recipient age, weight, and previous hepatic portoenterostomy did not. Current median follow-up values for total bilirubin and aspartate aminotransferase levels in the 154 surviving patients were 0.5 mg/dL and 34 international units/L, respectively., Conclusion: Long-term patient survival after orthotopic liver transplantation for congenital biliary atresia is excellent and is independent of recipient age, weight, or previous hepatic portoenterostomy. Optimal results are obtained in this patient population when liver transplantation is performed before marked hyperbilirubinemia, and when possible, using a living-donor graft.

With the growing shortage of available liver donors, many donors with risk factors that would have traditionally precluded liver procurement are now being considered. In this prospective study, we evaluated 50 "marginal" liver donors with pre-procurement abdominal ultrasounds and correlated results with findings at procurement and with subsequent allograft function. The results show that the ultrasounds have a specificity of 96% and a sensitivity of 68% in predicting abnormalities in donor livers that precluded transplantation. In addition, using ultrasound to screen marginal donors would result in significant savings in manpower and hospital resource utilization without "missing" any normal liver organs. Our results also show that, when properly selected, livers from donors with one or more high-risk factors function well with acceptable primary nonfunction rates.

The ligand-receptor binding requirements for achieving full B cell activation through the membrane immunoglobulin (mIg) signaling pathway are relatively demanding, and mIg-antigen engagements which fall below these critical thresholds cause, at most, only the partial activation of B cells. In an effort to resolve new means of enhancing the efficacy of mIgM-mediated signal transduction, as well as to further understand the process by which mIgM-mediated signals are initiated, we have explored the mechanism for a previously reported synergy between certain mixtures of murine anti-IgM mAbs in eliciting human B cell DNA synthesis. We here report that striking synergy occurs when any of several relatively high affinity mAbs specific for diverse domains of mIgM are combined in culture with the relatively low affinity C mu 4-specific ligand, mAb IG6. Although B cell activation was dependent upon the bivalency, and hence mIgM cross-linking potential, of the high affinity ligand, low affinity mAb IG6 could enhance the activation process when present as a monovalent Fab' fragment. This did not appear due to F(ab')2 contamination or Fab' aggregation, since IG6 Fab' preparations were notably compromised in several other functions requiring ligand bivalency. Pulsing studies revealed that the C mu 4-specific ligand exhibits its functional effects only when stimulatory mIgM receptor cross-links are being formed by bivalent ligands, and that IG6 Fab' enhancement is most notable during the later interval of the prolonged mIgM signaling process that leads to S phase entry. A unique region of the membrane-proximal IgM domain may be important for Fab'-mediated enhancement, since Fab' fragments that bind with higher affinities to distinct sites on C mu 4 were not as effective at mediating this phenomenon. Several possibilities for the adjuvant effects of this C mu 4-specific Fab' on B cell responses triggered by mIgM crosslinking ligands are discussed, including the possibility that IG6 Fab' influences the potential for mIgM dimer formation or interactions of mIgM with other signal-transducing molecules.

The domain binding specificity of 19 murine anti-human IgM monoclonal antibodies (MoAbs) that have shown considerable heterogeneity in the transduction of stimulatory and inhibitory signals to B lymphocytes was evaluated by competition radioimmunoassays. Through the use of: (i) enzymatic fragments of IgM which each encompass more than a single CH domain, i.e. Fc5 mu and F(ab')2 mu, (ii) isolated single domains, C mu 2, C mu 3, and C mu 4, and (iii) mu heavy chain disease proteins, nine anti-IgM MoAbs were found to have C mu 1 domain specificity, five to have C mu 2 specificity, and five others to have C mu 4 specificity. Ineffective binding to isolated mu chain demonstrated that C mu 1-specific MoAbs were directed to epitopes which require light chain for expression. The lack of binding of the C mu 4-specific MoAbs to CNBr cleavage fragments of Fc5 mu suggest that the determinants recognized by these MoAbs may also be conformational in nature. Cross-inhibition analyses were used to determine the number of unique epitopes recognized by the anti-IgM MoAbs. Results from these experiments showed that: (i) eight of the nine MoAbs specific for C mu 1 likely bind to a single epitope, or very proximate epitopes, (ii) the five C mu 2-specific MoAbs recognize at least three distinct epitopes, and (iii) the five C mu 4-specific MoAbs each recognize a separate determinant. A comparison of the known B cell activating properties of these MoAbs with their specificity for the various segments of the IgM molecule indicate that mitogenicity cannot be attributed to selective binding to any one domain.