Alterations in T and B lymphocytes in heart transplant patients early and late postoperatively.

Alterations in the percent and absolute number of thymus-derived (T) and bursa-equivalent (B) lymphocytes in peripheral blood were followed in 10 patients treated with antithymocyte globulin, prednisone, and azathioprine after cardiac transplantation. During the 1st postoperative wk the percent of T cells dropped below 10% in almost all cases (normal range, 65-91%) with a concomitant rise in the percent of B cells. However, the absolute T- and B-cell counts were both markedly depressed (less than 200 cells/mm3). During the 7-wk postoperative period the percent of T cells rose to 45-60% and the absolute count rose from 100 to 350 cells/mm3 (normal range, 1,092-2,400 cells/mm3). Although the percent of B cells was elevated (35-50%) during this period, the absolute B-cell count remained below the range of normals (268-640 cells/mm3). Follow-up of long-term survivors (3-60 mo postoperative) showed a continued marked T (467 cells/mm3) and B (95 cells/mm3) lymphocytopenia. Chronological relationships between the percent and absolute T-cell count and episodes of graft rejection in individual patients are discussed as possible adjuncts in the prediction of rejection crises.

Effects of alpha adrenergic blockade upon coronary hemodynamics.

The effect of alpha adrenergic block-ade on coronary blood flow regulation at rest was studied in 11 normally innervated patients and 8 cardiac allograft recipients by measuring arterial pressure and coronary sinus blood flow by thermodilution before and after alpha adrenergic blockade with phentolamine. Coronary vascular resistance was calculated by using coronary sinus blood flow and mean arterial pressure, and metabolic demand was estimated by the product of systolic arterial pressure and heart rate. In addition, the coronary sinus blood flow response to tachycardia was examined in 9 innervated patients and 12 denervated patients, with measurements repeated after phentolamine in 8 of the 9 innvervated patients and 6 of the 12 denervated patients. There was a 7.3+/-4.4% increase in coronary sinus blood flow in the innervated patients in response to alpha blockade, whereas the transplanted patients had an 8.2+/-1.8% fall in coronary sinus blood flow, despite equivalent changes in rate pressure product. The innervated patients also demonstrated a significantly greater increase in coronary sinus blood flow than did the transplanted patients during the first 5 s of an abrupt increase in heart rate (26+/-4 vs. 8+/-2.5 ml/min, P <0.001). This early response was blunted after alpha adrenergic blockade. We conclude that there is basal alpha adrenergic tone present on the coronary vasculature in man that is withdrawn by a sudden increase in heart rate.

The electrophysiologic effects of quinidine in the transplanted human heart.

Using His bundle recording techniques, we examined direct and autonomically mediated conduction system effects of quinidine in five cardiac transplant recipients who have anatomically denervated hearts. We made control conduction interval and refractory period measurements, and then infused 10 mg/kg quinidine gluconate over a 20-min period. At 30 min, we determined the electrophysiologic changes induced by quinidine. Quinidine significantly increased the atrial-His (AH) interval (from 97+/-9 [SEM] to 108+/-7 ms, P less than 0.001), the His-ventricular (HV) inteval (from 43.9 +/- 1 to 52.8 +/- 3 ms, P less than 0.01), the donor heart sinus cycle length (from 599 +/- 38 to 630 +/- 56 ms, P less than 0.08), and the atrial effective refractory period (from 214 +/- 14 to 241 +/- 11 ms, P less than 0.01). Quinidine significantly decreased the innervated, remnant atrial sinus cycle length (from 847 +/- 104 to 660 +/- 96 ms, P less than 0.01) and the blood pressure. The mean plasma concentration of quinidine at the time that electrophysiologic measurements were repeated was 4.37 +/- 0.449 micrograms/ml. We conclude that quinidine's predominant sinus nodal and atrioventricular nodal effects in man are autonomically mediated and opposite to its direct actions upon these structures. On the other hand, quinidine's prevailing effect on atrial refractoriness and His-Purkinje conduction in man is direct.

Role of tachycardia as an inotropic stimulus in man.

We examined the inotropic effect of tachycardia in nine postsurgical aortocoronary bypass graft patients (with intact cardiac innervation) and nine cardiac allograft recipients (with denervated hearts). The changes in stroke volume (SV) and velocity of circumferential fiber shortening (VCF) which accompany sudden increases and decreases in atrial pacing frequency were determined by computer-aided fluoroscopic analysis of the motion of surgically implanted midwall myocardial markers. Because the first beat after a change in rate retains the frequency characteristics of the preceding rate, we compared the first posttachycardia beat with control beats and late tachycardia beats with the first tachycardia beat; afterload and preload for each pair of beats were similar. For an increase in heart rate of 50 beats/min, SV and VCF rose 79 and 64% from the first tachycardia beat to late tachycardia beats, and SV and VCF rose 8 and 35% from control beats to the first posttachycardia beat in the innervated group. Responses in the denervated group were not significantly different from those in the innervated group. The degree of the inotropic response was positively correlated with the magnitude of the increase in heart rate (r = 0.91). The decay in augmented contractility after decreasing the rate back to control levels fits an exponential relationship with a mean t((1/2)) of 1.7 s. Thus, in conscious man, increases in heart rate represent a positive inotropic stimulus, independent of other factors influencing ventricular performance and unaffected by neural innervation, and should be considered when changes in cardiac function are interpreted during serial studies or after drug administration.

Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease: a prospective study.

BACKGROUND: This study examines the hypothesis that metabolic abnormalities of dysmetabolic syndrome are risk factors for transplant coronary artery disease (TxCAD). METHODS AND RESULTS: Sixty-six patients without overt diabetes, 2 to 4 years after surgery, underwent intracoronary ultrasound (ICUS), measurement of plasma glucose and insulin after oral glucose (75 g), and fasting lipid and lipoproteins. TxCAD incidence by angiography or autopsy was prospectively determined during subsequent follow-up (8 years). Coronary artery intimal thickness (IT) and subsequent outcomes were compared in patients stratified as having "high" versus "low" plasma glucose (>8.9 mmol/L) and insulin (>760 pmol/L) 2 hours after glucose challenge; and "abnormal" versus "normal" fasting lipid and lipoprotein concentrations as defined by the National Cholesterol Education PROGRAM: Patients with high glucose or insulin concentrations had greater IT: 0.38+/-0.05 versus 0.22+/-0.02 mm, P0.3 mm than with IT

Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study.

BACKGROUND: Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS: One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS: TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Long-term follow-up after surgical correction of Wolff-Parkinson-White syndrome.

The long-term efficacy of surgical correction of Wolff-Parkinson-White syndrome was evaluated in 45 consecutive patients. Before surgery, 42 patients had reciprocating tachycardia and 12 had atrial fibrillation. The principal operative procedure was endocardial incision in 42 patients, endocardial cryoablation in 2 patients and epicardial cryoablation without dissection of the atrioventricular (AV) fat pad in 1 patient. Two patients had perioperative complications. One patient had bleeding that necessitated reoperation, and one had a right cerebral stroke with subsequent clearing of neurologic deficit. At postoperative electrophysiologic study, only the patient who underwent epicardial cryoablation had conduction over an accessory connection. Two others had intermittent delta waves in the early postoperative period but no accessory connection conduction at electrophysiologic study. During a mean follow-up of 3.1 years, the patient with ineffective cryoablation had recurrent orthodromic tachycardia, and one other patient had late recurrence of delta waves without arrhythmias. Four other patients had frequent palpitation, which was caused by premature ventricular complexes in three and sinus tachycardia in one. Seventeen patients had occasional "skipped beats" without recurrence of tachyarrhythmias. Twelve of 13 patients whose arrhythmias limited employment before surgery returned to work after surgery. By actuarial analysis at 1, 2 and 3 years, all patients were alive and 98% were free from tachyarrhythmias. Surgical correction of Wolff-Parkinson-White syndrome provides excellent long-term results with low morbidity. Patients who are disabled by arrhythmias return to work after successful surgery. Delta waves may persist or recur without return of arrhythmias. Minor postoperative episodes of palpitation are common and do not correlate with tachyarrhythmias.

Comparison of defibrillation efficacy in humans using a new catheter and superior vena cava spring-left ventricular patch electrodes.

The automatic implantable cardioverter-defibrillator currently utilizes an electrode system that requires a major operation for implantation. Effective defibrillation using an implantable cardioverter-defibrillator catheter positioned transvenously would eliminate the morbidity associated with such surgery. Fifteen patients undergoing defibrillator implantation were studied to compare the efficacy of the catheter with that of the superior vena cava spring (6.7 cm2, anode)-left ventricular patch (13.5 cm2, cathode) electrode system using truncated exponential waveforms with 60% tilt. The catheter is 11F in diameter and tripolar. A distal platinum-iridium tip used for pacing was separated by 4 mm from a middle 4.3 cm2 platinum electrode; these were positioned at the right ventricular apex. The proximal 8.5 cm2 platinum electrode was situated at the superior vena cava-right atrial junction. Defibrillation was performed using the middle (cathode) and proximal (anode) electrodes. Ventricular fibrillation was induced by alternating current six times, and defibrillation shocks of 1, 5, 10, 15, 20 or 25 J were given in random order, first using the catheter and then the spring-patch system. Rescue shocks of higher energy were given if there was failure. Although very low energy levels appeared to be slightly more efficacious when using the spring-patch system, there was no statistically significant difference between the electrode systems for any of the energies tested. Permanent implantation of the catheter would have been suitable in 45% of the patients, as compared with 54% of patients with the spring-patch system (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Early development of accelerated graft coronary artery disease: risk factors and course.

OBJECTIVES: This study assessed the time of first appearance of angiographic graft coronary artery disease in relation to clinical and laboratory variables and clinical events in heart transplant recipients. BACKGROUND: Graft coronary artery disease is the main factor limiting long-term survival after heart transplantation, and it is important to understand its natural history. METHODS: One hundred thirty-nine consecutive patients who developed angiographic coronary artery disease after heart transplantation were classified according to early (< or = 2 years) versus late (> 2 years) posttransplantation initial detection of coronary artery disease. These subgroups were analyzed for differences in clinical and laboratory demographics, incidence of progression to ischemic events and incidence of antecedent cytomegalovirus infection. RESULTS: The early-onset group (64 patients) had more rapid progression to ischemic events than the late-onset group (75 patients), with 59% of the late group and only 35% of the early group free from ischemic events by 5 years after initial detection (p = 0.02), but there were no significantly correlated clinical or laboratory predictors of ischemic events. The early group had a significantly higher incidence of antecedent cytomegalovirus infection. CONCLUSIONS: We conclude that 1) accelerated graft coronary artery disease develops at variable times after heart transplantation; 2) the early appearance of graft coronary artery disease may be a marker of intrinsically more aggressive disease; 3) cytomegalovirus infection is associated with earlier onset of graft coronary artery disease. Patients with early development of graft coronary artery disease should potentially be given priority for interventional strategies as they are developed.

T-lymphocyte rosette inhibition titering of antisera by direct microassay.

A 60-sample micro-rosette inhibition assay for determining the 100% rosette inhibitory titers of heterologous antisera is described. The assay is performed in histocompatibility trays, under oil, using frozen-thawed thymocytes or peripheral blood lymphocytes for an appropriate period, either with or without added complement; SRBC are inoculated into each well, and rosettes formed by centrifugation of the trays at 200 x g. following centrifugation, glutaraldehyde is added to each well to fix rosettes to the well bottom and the plates inverted to allow unbound SRBC to fall away. One hundred percent rosette inhibition is determined by low power microscopic examination of the inverted wells. Highly reproducible in-assay (+/-4% average standard error) and between-assay (+/-9%) inhibition values are obtained which correlated well (r = 0.99) with values calculated by more conventional methodology.

Infectious complications in heart-lung transplant recipients.

Infectious complications were studied in 14 patients who received heart-lung transplants at Stanford University Medical Center from March 1981 to November 1983. Twenty-nine infections occurred in 12 patients: 18 bacterial, nine viral, and two fungal. Sixteen (89 percent) of the bacterial infections occurred in the lung. Because of frequent colonization of the lower respiratory tract, the specificity of transtracheal aspiration and bronchoscopy was low. Empiric broad-spectrum antibiotic therapy was usually successful, and no patient died of bacterial infection. Cytomegalovirus infection occurred in six and herpes simplex virus infection in three patients. Two patients had invasive candidiasis at postmortem examination. This series emphasizes the importance of infection, particularly of the lung, in causing morbidity and mortality in heart-lung transplant recipients.

Coronary bypass surgery for unstable angina pectoris. Clinical follow-up and results of postoperative treadmill electrocardiograms.

The first 81 patients who underwent coronary artery bypass surgery at Stanford University Hospital for unstable angina pectoris have been followed up for an average of 18 months. The over-all surgical mortality was 8.6 per cent (seven patients). There have been no operative deaths in last 32 patients, which may be due to over 75 per cent of these patients being stabilized on intensive medical therapy from 24 to 72 hours before study or surgery. There was a 16 per cent (13 patients) perioperative and 15 per cent (12 patients) late incidence of myocardial infarction. Of 74 patients who survived the initial operation 2 died 2 and 3 months postoperatively. Good or complete relief from pain was obtained in 94 per cent (70 patients) of the survivors. Of 57 longterm survivors tested, 49 per cent (28 patients) had a definite ischemic response to treadmill exercise testing. This may reflect the severe nature of the occlusive coronary disease or mechanisms other than increased coronary flow being responsible for the relief of pain. Although coronary bypass surgery appears to be effective in relieving the pain of patients with unstable angina pectoris, the 18 month average follow-up indicates that the incidence of myocardial infarction in surgically treated patients is comparable to that in medically treated patients.

Coronary artery spasm in the denervated transplanted human heart: a clue to underlying mechanisms.

The mechanism of coronary artery spasm has been poorly understood but there has been some suggestion that cardiac autonomic innervation may play an important role. We report coronary artery spasm in a 43 year old man two years after he had received a transplant. Provocative pharmacologic testing suggested functional denervation of the patient's heart. Thus, coronary artery spasm can occur in the transplanted, denervated human heart. Autonomic innervation of the heart is not essential in all cases of coronary spasm, and circulating catecholamines and/or metabolic of hormonal products may play an important role.

Significance of thyroid dysfunction in human cardiac allograft procurement.

Twenty-two potential cardiac allograft donors had evaluation of thyroid function performed just prior to cardiectomy. Despite statistically significant abnormal thyroid function, no correlation to graft function or failure was observable. Multiple myocardial microinfarcts, undetected at the time of donor selection were detected in two hearts that were abandoned prior to transplantation and possibly another heart that failed as an allograft in a heart-lung transplant recipient.

Sequential orthotopic heart transplantation in man.

Between January 1968 and March 1980, 202 hearts had been transplanted into 185 patients at Stanford University Medical Center. Occasionally, patients after transplantation develop myocardial failure which is amenable only to retransplantation. Sixteen patients underwent initial orthotopic allograft using standard techniques. Eight patients developed accelerated arteriosclerotic coronary disease, six had unrelenting rejection, and two had donor heart dysrrhythmia or right ventricular failure requiring retransplantation. One patient required a third transplant because of donor left ventricular ischemia. All sequential transplants were managed similarly to the primary transplant. Of the initial transplant hearts at risk, 60% survived for more than 1 year, and 57% survived for more than 2 years. These results are similar to those of patients not requiring retransplantation. Of the secondary transplant hearts at risk, 31% survived for more than 1 year and 29% survived for more than 2 years. The severity of infection and/or rejection contributed most significantly to secondary heart transplant mortality. Sequential orthotopic cardiac transplantation offers an acceptable alternative to patients with allograft failure. Survival is not as favorable as with initial transplantation because of the prolonged immunosuppression during sequential transplantation.

Use of rabbit antithymocyte globulin in cardiac transplantation. Relationship of serum clearance rates to clinical outcome.

Serum rabbit globulin (RG) clearance rates were determined in 30 consecutive cardiac transplant recipients by radioimmune assay of serum RG levels after completion of an initial postoperative course of rabbit anti-human antithymocyte globulin (RATG). Twenty patients, who exhibited rapid RG elimination rates (average half-life, 1.6 days), had a rejection onset time of 16.2 days rejection frequency of 3.9 episodes/100 patient days, and a 1-year survival rate of 59%, respectively, as compared with 28.3 days, 1.9 episodes/100 patient days, and 80%, respectively, for the 10 patients with more prolonged initial RG elimination rates (average half-life, 11.4 days); Nineteen patients received one or more repeat courses of RATG. In 16 of these a progressive increase in RG half-life during subsequent RATG administration could be demonstrated. A close correlation was observed between total RATG doses given in the initial course and peak serum levels of RG obtained (r = 0.82) and between onset of rejection and initial t1/2 RG (r = 0.69). This latter correlation was improved by the elimination of one of the 30 patients (r = 0.81) or by considering only those patients treated from a single RATG batch (r = 0.85; n = 15). No significant relationship was detected between any of the parameters assayed and (1) total RATG dose, or (2) rosette inhibition titers of RATG administered. Survival and rejection parameters of the first 30 patients receiving RATG were compared with the previous 20 receiving equine antithymocyte globulin; these 50 comprising the entire population in which rejection was confirmed by cardiac biopsy. Rejection onset was 20 versus 12 days, rejection frequency was 3.1 versus 5.0 episodes/100 patient days, and graft survival at 1 year was 66 versus 41% for the RATG-equine antithymocyte globulin-treated patients, respectively. From these data it was concluded that (1) RATG administration favorably affects transplantation outcome; (2) RATG half-life, as reflected by RG clearance rates, was the most important variable governing RATG effectiveness, (3) variation in rosette inhibition titers within RATG batches made in the same fashion from large rabbit pools were of minimal clinical importance; and (4) monitoring of serum RG levels provided a necessary and rational basis for effective modulation of immunosuppressive therapy.

Preparation, characterization, and primate testing of monoclonal antithymocyte globulin.

Monoclonal antibodies specific for T cells from both the human and rhesus primate species were detected by their ability to inhibit T cell rosette formation with sheep erythrocytes. The antibodies were shown by fluorescence techniques to react with all thymocytes and peripheral blood T cells but not to B cells, monocytes, platelets, or erythrocytes. Rosette inhibition titers of these antibodies were 30-fold lower when rhesus, rather than human T, cells were used as the rosette-forming cell in assay. Nonetheless, two monoclonal antibodies, of the IgG3 isotype, termed antithymocyte monoclonal (ATM) e.1 and 2.2, were shown to depress selectively circulating T cells to nondetectable levels following single dose administration to rhesus primates and to prolong skin allograft survival in a rhesus primate given a 6-dose course of treatment. The rhesus primates suffered no ill effects and no peripheral blood cellular component other than T cells was depressed. Monoclonal antibody secreting hybridoma cells are capable of producing ATM 3.1 and 3.2 in quantity when grown as peritoneal tumors in selected mouse hybrids. Purification of ATM 3.1 or 3.2 is easily accomplished by affinity chromatography on protein A. These properties suggest that ATM antibodies may become useful immunosuppressive agents in clinical transplantation.

Prophylactic ganciclovir treatment reduces fungal as well as cytomegalovirus infections after heart transplantation.

Cytomegalovirus (CMV) infection is associated with an increased incidence of other opportunistic infections in organ transplant recipients. Whether this is related to immunomodulating effects of CMV or independent of CMV but associated with a host risk factor common to both infections is unclear. The purpose of this study was to determine whether the reduction in CMV infections seen with prophylactic ganciclovir treatment after heart transplantation is associated with a reduced incidence of other opportunistic infections. Of 149 patients prospectively enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of ganciclovir to prevent CMV disease, 74 patients enrolled at this center (33 control and 41 ganciclovir-treated) were retrospectively identified. All received prophylactic OKT-3 and standard 3 drug maintenance immunosuppressive therapy. Actuarial survival and rejection rates and incidence of opportunistic infections (bacterial, fungal, and protozoal) for the 2 treatment groups were determined and compared using Cox-Mantel analysis. CMV disease occurred 2.5 times more frequently in the control group. There were no significant differences in survival or rejection rates nor in bacterial or protozoal infection incidence between the 2 groups. Bacterial infections occurred in 54% of control and 39% of ganciclovir-treated patients (P = 0.18). There were significantly fewer fungal infections in the ganciclovir-treated group (7% vs. 27%, P = 0.0071). CMV and fungal infections were both significantly reduced in patients who received ganciclovir prophylaxis. This suggests that active CMV disease may be causally associated with the development of opportunistic fungal infections.

Cardiac allograft survival in rhesus primates treated with combined total lymphoid irradiation and rabbit antithymocyte globulin.

Eighteen abdominal heterotopic cardiac allografts were performed in outbred rhesus primates. For immunosuppression seven animals received six 100-rad/day total lymphoid irradiation (TLI) doses the week preceding transplant and three 3-mg/kg i.m. rabbit antithymocyte globulin (RATG) doses on postoperative days -1, 0, and +1; five animals were given this RATG dose but no irradiation; three were given TLI alone; and three were given no immunosuppressive therapy. Circulating T lymphocyte counts were monitored in all animals (rosettes). Graft survival in the combined TLI-RATG therapy group (169 +/- 15 days) was significantly greater than in untreated (11 +/- 1 days), RATG alone (22 +/- 12 days), or TLI alone (38 +/- 6 days) treated animals (P less than 0.001, 0.0001, and 0.001, respectively). The animals receiving combined TLI-RATG therapy also achieved significantly greater and more prolonged T lymphopenia than that obtained in the other three groups. Six of seven cardiac allografts placed in animals receiving TLI-RATG therapy were removed electively before cessation of electrical activity; however, in four of these rejection pathology was noted. Thus, it seems that combined TLI-RATG therapy may be of benefit in the management of transplant recipients, but its use will probably not abolish these patients' requirements for immunosuppressive maintenance measures.

Radioimmune assay of heterologous serum gamma-globulin in patients receiving rabbit antihuman thymocyte globulin.

A radioimmune assay (RIA) method for detecting heterologous serum rabbit gamma-globulin (RG) and antibody to this protein is described. The methodology is used for monitoring serum levels of rabbit globulin in patients receiving rabbit ATG (RATG). In 7 cardiac recipients receiving RATG, maximum serum levels of RG were achieved 1-3 days after administration of final dose. RG half-life subsequent to peak serum levels was rapid (X = 36 hr) in 4 patients and prolonged (X = 18 days) in 3 patients. Patient antibody to rabbit gamma-globulin was detectable only in those patients with short RG half-life. Antirabbit antibody titers in these patients were extremely low and barely detectable by RIA.