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Administration of five daily doses of 15 mg/kg Cyclosporine on the day before, the day of, and three days after, renal transplantation prolonged the survival of Buffalo (BUF) renal allografts in Wistar-Furth recipients from a mean survival time (MST) of 7.9 +/- 0.74 to 25.5 +/- 1.2 days. The immunologic effects of this brief cyclosporine course were assessed using spleen cells harvested five days after transplantation. Cyclosporine abrogated both the direct lymphocyte-mediated cytolysis of donor 51Cr-labelled BUF targets, and the early, three-day enhanced proliferation, and it stimulated lympholysis of labelled donor cells markedly after restimulation in vitro with BUF lymphocytes. Therefore, cyclosporine disrupts the maturation of both proliferative and cytotoxic precursors of the alloimmune response. A potentially synergistic effect of soluble donor antigen with cyclosporine was postulated, because 3 M KCl extracts are capable of directly stimulating both suppressor T cells and helper T cells. Because the activity of T helper cells appeared in these experiments to be dampened by cyclosporine, antigen stimulation of suppressor cells could lead to unresponsiveness. On the day prior to transplantation, 5 mg of a 3 M KCl extract of BUF spleen (Ag) was administered intravenously in addition to the cyclosporine regimen. Although there was no difference in the overall survival of grafts in the Ag-cyclosporine group and the cyclosporine only group, the Ag-cyclosporine regimen did prolong graft survival significantly in the subset of animals with grafts functioning more than 35 days (Ag-cyclosporine MST = 109.5, cyclosporine alone MST = 54 days). Therefore, it may be possible to exploit the selective properties of cyclosporine and of soluble antigen treatments to achieve unresponsiveness without the hazards of continued administration of immunosuppressive agents.

Injection of purified human interleukin 2 (IL-2) directly into the spleen has been shown to potentiate the effect of specific chemoimmunotherapy, using butanol-extracted tumor-specific transplantation antigen (TSTA) and cyclophosphamide (CY) in a C3H/HeJ murine methylcholanthrene-induced fibrosarcoma model. Since IL-2 has a relatively short half-life in serum, continuous infusion of this lymphokine via the intrasplenic (i.s.), i.v., or i.p. routes was administered in an attempt to maintain therapeutic tissue levels. Primary hosts bearing 7-day (4-mm) or 14-day (greater than 10-mm) established s.c. methylcholanthrene F tumors were treated with weekly s.c. doses of 1 micrograms 1-butanol-extracted, isoelectrophoretically purified TSTA, the first of which was combined with a single i.p. injection of 20 mg/kg CY, and/or a 10-day continuous infusion of 120 units IL-2/day by one of the three routes. IL-2 delivered by all routes either by continuous infusion or by bolus injection augmented the chemoimmunotherapeutic efficacy of TSTA/CY against 7-day established tumors. On the other hand, the outcome of 14-day (greater than 10-mm) established tumors depended upon the method and route of administration of IL-2: continuous infusion via the i.v., i.p., or i.s. route prolonged host survival beyond that obtained by bolus administration. Continuous i.s.-IL-2 infusion greatly prolonged, continuous i.p.-IL-2 (120 units/day) slightly extended, and continuous i.v.-IL-2 had no effect on host survival. In a spontaneous pulmonary metastasis model following amputation of a tumor-bearing limb, only the triple regimen of TSTA/CY/i.s.-IL-2 decreased the number of lung colonies and prolonged host survival. Continuous infusion i.s.-IL-2 (120 units/day, 10 days) combined with TSTA/CY induced tumor-specific cytotoxic T-cells, as documented by in vitro 51chromium release cytolytic and in vivo local adoptive transfer assays. Based upon the residual local adoptive transfer assay activity of spleen cells depleted of specific lymphocyte subpopulations using monoclonal antibodies, the immune effectors generated by i.s.-IL-2 plus TSTA/CY bear the Thy 1+, Lyt2+ phenotype and those by i.p. or i.v.-IL-2 plus TSTA/CY, the Thy+, L3T4+ markers. Thus continuous i.s.-IL-2 infusion appears to augment cytotoxic T-cell induction in tumor-bearing hosts undergoing stimulation of helper elements by TSTA and inhibition of suppressor cells by CY.

The use of percutaneous endourological techniques is demonstrated in recipients of renal allografts. Transplant complications that previously had required prompt surgical intervention may be approached safely by the judicious use of percutaneous manipulations. While examples of perirenal hematoma, renal abscess, urinary fistula and renal pelvic stone extraction are presented, close patient observation and a low threshold for surgical intervention are recommended to permit the continued, safe evaluation of this approach.

With the advent of cyclosporine A, heart transplantation has become a widely accepted treatment for patients with end-stage cardiac disease that is not amenable to medical or surgical treatment. Between July 1982 and December 1985, 86 heart transplantations were performed at the Texas Heart Institute with cyclosporine A and prednisone used for immunosuppression. Thirty patients had complications requiring general surgical consultation. The pancreas and biliary tracts were most commonly affected. Pancreatitis developed in sixteen patients; five patients required operative intervention, resulting in a 40% mortality rate. Five of nine patients with cholecystitis required cholecystectomy. All patients survived the procedures. Other gastrointestinal complications included colonic ileus, bowel perforation, gastrointestinal bleeding, gastric outlet obstruction, and perirectal abscess. Patients who have undergone cardiac transplantation are susceptible to life-threatening infections and are at risk of serious complications requiring general surgical intervention. Better results can be obtained in these complex clinical situations when complications are identified early and managed aggressively through the adjustment of immunosuppression, adequate selection of antimicrobial agents, and proper timing of surgical intervention.

Combination therapy with a short course of cyclosporine (CsA) on the day prior to, to day of, and the day after transplantation and one dose of 5 mg 3M-KCl-extracted donor-soluble antigen (Ag) prolongs the survival of Buffalo (Buf, RT1b) kidney allografts in Wistar-Furth (WFu, RTu) inbred rats because of the induction of specific suppressor cells. Four systems were utilized to demonstrate suppressor cell activity in vivo. First, pooled lymphocytes from CsA-Ag-treated hosts suppressed the capacity of admixed, syngeneic WFu cells to display an in vivo mixed lymphocyte culture reaction toward donor Buf, but not third-party Brown-Norway (BN, RT1n), hosts. Second, systemic adoptive transfer two days prior to, or on the day of, transplantation of 5 x 10(8) putative suppressor cells harvested ten days after combined Ag-CsA treatment prolonged graft survival slightly but significantly from 7 to 9 days in virgin, secondary hosts. Third, admixture of 5 x 10(8) cells from Ag-CsA-treated hosts vitiated the capacity of 5 x 10(8) virgin WFu spleen cells to restore the capacity of recipients sublethally irradiated with 500 rads to reject. Buf allografts at 7.9 days rather than 16.7 days. Fourth, i.p. administration of low-dose cyclosphophamide (CY) 7 days after transplantation, a regimen known to inhibit suppressor cells, reduced the capacity of the Ag-CsA regimen to prolong graft survival. Two additional cycles of CsA therapy at 10-day intervals administered in an attempt to maintain T suppressor dominance over T helper cells prolonged median graft survival to 65 days. Similar prolongation was not achieved using donor blood transfusion as the immunogen, or using cycles of CsA alone. These findings suggest that 3M KCl donor antigen amplifies the induction of specific suppressor cells, and that CsA by virtue of helper T cell inhibition facilitates the establishment of suppressor cell dominance, eventually leading to host unresponsiveness.

The balance of immunoregulatory T-helper (TH) and T-suppressor (Ts) lymphocytes was assessed in recipients of living donor and cadaveric grafts treated with azathioprine (Az) or cyclosporin A (CyA). Enumeration of each subpopulation was performed with monoclonal OKT antibodies. While Az-treated patients had a normal ratio of circulating peripheral blood helper-inducer (OKT4+) to suppressor-cytotoxic (OKT8+) cells, recipients treated with CyA showed a reduced ratio resulting from a decreased number of TH cells with normal numbers of Ts cells. The functional activity of Ts cells was evaluated by their capacity to suppress the primary mixed lymphocyte culture response of a normal, unrelated individual. Az-treated recipients showed greater suppression than the CyA-treated group, hemodialysis patients, or normal individuals. The function of TH cells was evaluated by the capacity of isolated patient peripheral blood T cells to promote pokeweed mitogen--driven immunoglobulin release by normal B cells, which then produced hemolytic plaques.l TH function was depressed in CyA-treated but not Az-treated recipients as compared with normal individuals. These results demonstrate distinctive profiles of immunoregulatory cells in patients immunosuppressed with Az or CyA. On the one hand, successfully engrafted Az-treated patients showed enhanced suppressor-cell activity with normal helper activity. On the other hand, CyA-treated patients had reduced helper-cell function with activity. On the other hand, CyA-treated patients had reduced helper-cell function with modestly increased suppressor-cell activity. These findings may provide guidelines for the selection of and parameters for monitoring the therapeutic efficacy of immunosuppressive agents in allograft recipients.

Since the mode of action of cyclosporine (CsA) in man is incompletely understood, there are no monitoring tools to assess immunosuppressive effect in vivo. In vitro CsA inhibits lymphoproliferation in response to allogeneic and mitogenic stimuli, presumably due to reversible suppression of T helper cell generation of interleukin-2. Therefore the present studies examined the immunosuppressive effect of patient sera on a third-party mixed lymphocyte reaction (MLR) as a pharmacodynamic approach to quantify patient responses to CsA administration. Four kinetic patterns of in vitro immunosuppressive activity were discerned: 24/28 (86%) patients showing two cycles of MLR inhibition--namely, a first peak corresponding to absorption of CsA and an independent second peak of immunosuppression (type I), were free of rejection; while 17/23 (74%) patients demonstrating one cycle corresponding to the peak of CsA absorption (type II) suffered rejection episodes (P less than 0.001). In addition, 20 patients generating continuously high levels of in vitro serum activity (type III) were almost all free of rejection, but manifested nephrotoxicity; while two patients showing continuously low levels (type IV) suffered graft loss due to irreversible rejection (P less than 0.01). Thus failure to display either a second peak or continuously high levels of MLR inhibition was associated with a markedly increased incidence of rejection (76% versus 16%). The in vitro functional characteristics of peak-2 were similar to those of CsA, as assessed by the kinetics of inhibition of MLR lymphoproliferation or cell-mediated lympholysis (CML), and by gross chemical properties of partitioning into organic solvents and heat stability. These findings suggest that pharmacodynamic analysis by MLR inhibition not only affords a useful parameter of immunosuppression, but also may provide an in vitro model to dissect the generation and biotransformation of active CsA metabolites.

The technique of creating an upper arm side-to-side A-V fistula in patients with forearm vascular access failures has been described. The procedure has been used extensively in patients in Japan with a high degree of success. The limited U.S. experience has confirmed that the procedure results in trouble-free, reliable vascular access. It is proposed as an alternative approach for patients with forearm access failures.

The therapeutic efficacy of cyclosporine (CsA) as an immunosuppressive agent was complemented by a modest, long-term incidence of toxic complications in 402 renal allograft recipients engrafted one to five years prior to analysis. The overall patient and graft survivals at one year were 97% and 84% (actual), and at five years 92% and 67% (actuarial). The immunosuppressive therapeutic index was excellent: only 12% of allografts were lost from rejection, with 5% of patients succumbing to infection. While infections were common, tending to emanate in the urinary tract or to be viral in etiology, they were generally mild and readily controlled. Only four patients displayed malignancies; none succumbed to this cause. The most common toxic complication was hypertrichosis, which was accentuated in pediatric patients. While tremors occurred in 20% of patients, primarily during the first three months, other neuroectodermal complications of parethesias, depression, somnolence, and seizures were rare. Hepatotoxicity, which was noted in 50% of patients, particularly recipients of cadaveric grafts, generally was first seen as a transaminase elevation, at least partially reversible by dose-reduction and abating by the third year. Associated disturbances of cholelithiasis and pancreatitis were occasionally observed. Nephrotoxicity was the only persistent, long-term complication. Hypertension occurred in 72% of patients during the first month, 36% in the second year, and about 15% thereafter. Hyperuricemia, which occurred in about 30% of recipients during the first two years, was occasionally associated with symptomatic gout. The mean serum creatinine level remained elevated throughout the follow-up period at 1.8-1.9 mg/dl, suggesting persistent, but nonprogressive, drug-induced renal injury. The present analysis documents the relative safety of CsA for long-term therapy, and highlights the need for new approaches to ameliorate drug-induced nephrotoxicity.

Although cyclosporine (CsA) therapy has improved the outcome of allotransplantation, drug-induced nephrotoxicity presents a potentially serious complication in a significant proportion of patients. The nephrotoxic injury, which may present acutely in the peritransplant period, subacutely in the first few months, or chronically, may be caused by toxic effects at various levels of the nephron: arteriole, glomerulus, and/or proximal tubule. The nephrotoxic picture of decreased glomerular filtration rate, impaired urea secretion, hyperkalemia, hypertension, and tubular dysfunction with preserved sodium reabsorption occurs not only in the renal allotransplant setting, wherein it obscures the diagnosis of rejection, but also in recipients of other grafts and patients under treatment for autoimmune disease. Because conversion from CsA to other immunosuppressive agents carries a high risk of rejection and allograft loss (or recrudescence of autoimmune disease), the present management strategy uses cautious CsA does reduction with concomitant institution of full-dose azathioprine (Aza) therapy. Definition of pharmacokinetic and pharmacodynamic properties that predict patients at risk for nephrotoxic complications may lead to new CsA dosing regimens yielding an improved therapeutic index.

Local adoptive transfer assays (LATA) were used to analyze and compare the progression of the immune response in C3H/HeJ mice to irradiated tumor cell vaccine and to crude 3M KCl solubilized antigens extracted from a syngeneic methylcholanthrene-induced fibrosarcoma. Sequential LATA performed 2, 6, 9, 12 and 15 days after soluble antigen pretreatment of spleen cell donors revealed a sinusoidal evolution of lymphoid cell activity. An initial brief period of potent tumor facilitation (days 6-9) was followed by a phase of tumor neutralization (days 9-12) which decayed by day 15. On the other hand, spleen cells from donors sensitized with irradiated tumor cells exhibited consistent tumor neutralization which was sustained throughout 15 days. Thus the tumor growth facilitation observed only in CSA-treated donors may represent a qualitative difference in the immune state induced by soluble, as opposed to cellular, forms of tumor antigen.

This report examines the effect of pretransplant (pre-Tx) blood transfusions (BT) on the patient and graft survival results of 320 cyclosporine (CsA) and prednisone (Pred)-treated primary (1 degree) recipients of cadaveric (CAD) donor renal allografts. The 320 CsA-Pred treated 1 degree-CAD recipients included 100 pre-Tx untransfused (O-BT) and 220 transfused patients. The overall patient survival at 12, 24, and 36 months post-Tx were 94%, 94%, and 93%, respectively. There were no differences observed in graft survivals at 12, 24, or 36 months post-Tx whether patients received 0, 1-4, greater than or equal to 5-10 or greater than 10 pre-Tx BTs. A mean serum creatinine of 1.9 +/- 0.7 mg/dl was comparable among all BT groups at 12, 24, and 36 months post-Tx. The frequency of rejection episodes--namely, 37% for O-BT and 36% for greater than O-BT were identical. High-risk patients (greater than 45 years of age, diabetics, or blacks) were comparably distributed in O-BT and greater than O-BT groups and did not impact on the data. Similarly, increasing panel-reactive antibodies (PRA), associated with increasing numbers of pre-Tx BTs, did not influence the data. When HLA A, B, and DR matching results were combined with the BT groupings no differences were observed in patient or graft survivals. Poorly matched and untransfused recipients did as well as well-matched, transfused recipients. These findings suggest that CsA-Pred immunosuppressive therapy allows for successful 1 degree-CAD renal allograft transplantation without the need for pretransplant blood transfusion conditioning or matching of donor HLA A, B, and DR antigens to recipients.

From June 1977 to March 1985, 572 renal transplants were performed at The University of Texas Medical School at Houston. This represented 220 patients (151 cadaveric [CAD] and 69 living-related donor [LRD] recipients) treated with azathioprine and prednisone (Aza-Pred) and 352 patients (250 CAD and 102 LRD) treated with cyclosporine (CsA) and Pred. Sera from each recipient before and after transplant (Tx) as well as from each of their 436 donors (265 CAD and 171 LRD) were retrospectively tested for the presence of antibody to the human T cell lymphotrophic virus type III (HTLV-3) by enzyme immunoassay (EIA) and Western Blot analysis. Of the 436 donors tested, only 1/265 (0.38%) CAD donors were both EIA repeatedly reactive and Western Blot positive, whereas none of the 171 LRD were reactive. Pre-Tx, 4/401 (1.0%) CAD and 1/171 (0.6%) LRD recipient sera were EIA repeatedly reactive, however, all 5 were to be Western Blot negative. Post-Tx, 4.2% of the sera (24/572, 4 LRD and 20 CAD recipients) were EIA-reactive. All 20 CAD recipient sera were subsequently found to be negative with Western Blot testing. However, 2 LRD sera (2/572, 0.35%) displayed EIA reactivity as well as Western Blot positivity. One LRD, Western-Blot-positive recipient is alive and well with a functioning allograft 39 months post-Tx, whereas the second LRD, Western Blot positive recipient died of septic complications 16 months post-Tx. Finally, the recipient of the Western-Blot-positive CAD allograft is alive with a well-functioning graft and remains EIA and Western-Blot-negative 36 months post-Tx.

The nonionic detergent octyl-beta-D-glucopyranoside (C8Glu) was used to extract immunogenic tumor-specific transplantation antigen (TSTA) from intact cells and purified plasma membranes of the 3-methylcholanthrene-induced fibrosarcoma MCA-F. Pretreatment of syngeneic C3H/HeJ mice with 100 micrograms of C8Glu extracts induced specific immunoprotection such that mice resisted the outgrowth of MCA-F but not the antigenically distinct tumors MCA-D or MCA-2A. Incubation of intact cells with 7 mM (0.2%) C8Glu for 30 minutes at 23 degrees C was judged to be noncytolytic because extracted cells excluded trypan blue. Preparative isoelectric focusing partially purified the MCA-F-specific antigen from crude C8Glu extracts into the pH 6.5-6.8 region of the gradient. Electrofocusing yielded 60% of the applied antigen activity and a fourfold to fivefold increase in specific activity. In addition, immunoprotective activity was obtained in 2% C8Glu extracts of MCA-F plasma membranes, confirming the membrane localization of the MCA-FTSTA. Three properties of C8Glu rendered it an attractive agent for the preparation of cell surface proteins: a nonionic character, large critical micellar concentration, and its capacity to extract antigens without complete membrane solubilization or cell disruption.

Cyclosporine (CsA), a powerful immunosuppressive agent that increases graft survival in renal transplant recipients, is often nephrotoxic. The clinical distinction between acute rejection and CsA nephrotoxicity (NT) is a common challenge in the management of these patients. To seek a histologic distinction between acute rejection and CsA-NT, we reviewed the renal biopsies performed prior to initiation of therapy for rejection or nephrotoxicity in two groups of patients. Group 1 (ten patients) had criteria consistent with acute rejection and responded to steroid pulse therapy. Group 2 (15 patients) was treated for CsA-NT and responded to a decrease in the dose of CsA. We conclude that CsA-NT has no specific histologic features. A prominent interstitial mononuclear cell infiltrate as well as tubulitis are features of acute cellular rejection. These findings do not exclude the possibility that rejection and CsA-NT can co-exist in the same patient.

The number of pretransplant blood transfusions (BT) from random donors influences the recipient's immune response status and suppressor cell number and function, as well as allograft survival. The 54% one-year survival rate for 104 cadaveric renal allograft recipients treated with azathioprine and prednisone was divisible into two groups: 74.5% in 51 patients receiving greater than 5 BT and 34% for 53 patients with less than 5 BT (P less than 0.02). Transfusions enhanced the benefit of HLA A, B, and DR compatibility on graft survival: 33 recipients of well-matched grafts (less than 2 A, B, and 0-1 DR mismatches) had a one-year survival rate of 94% when pretreated with greater than 5 BT, compared with 38% when receiving less than 5 BT (P less than 0.05). The graft survival of 73% (36/49) displayed by patients determined preoperatively to be weak immune responders was significantly better than the 36% survival (20/55) demonstrated by strong immune responders (P less than 0.01). The transfusion history correlated with immune responder status: 76% (39/51) of patients receiving greater than 5 BT were weak immune responders, whereas 81% (43/53) of patients receiving less than 5 BT were strong immune responders (P less than 0.001). Ninety-two percent (12/13) of patients with greater than 5 BT, but only 58% (10/17) of patients with less than 5 BT, had a normal number of OKT8+ T suppressor cells. Only 1 X 10(5) mononuclear cells from patients with greater than 5 BT rather than 4 X 10(5) cells from patients with less than 5 BT caused 50% suppression of a third-party MLC. Thus, patients receiving greater than 5 BT are more likely to display weak immune responses, normal numbers of OKT8 cells, strong suppressor function in vitro, and prolonged allograft survival.

A 57-year-old woman with mycosis fungoides that had failed to respond to cytotoxic chemotherapy was treated with cyclosporine. Mycosis fungoides and Sézary syndrome are disorders of helper T cells. Cyclosporine is a fungal endecapeptide of novel chemical structure that causes preferential inhibition of T helper cells. Because of this in vitro inhibition of T helper cells, we used cyclosporine to treat a patient who had mycosis fungoides that was refractory to cytotoxic combination chemotherapy. With cyclosporine administered initially as an intravenous infusion and orally after 10 days, there was immediate improvement in the patient's symptoms. This subjective improvement was accompanied by a decrease in her skin infiltration, noted on physical examination and microscopically. Despite continued administration of the cyclosporine, symptoms recurred after 3 1/2 months of therapy.

Intravenous digital subtraction angiography (IV-DSA) combined with excretory urography was used to evaluate the renal anatomy of 100 potential living-related kidney donors. Each of the 100 patients underwent subsequent nephrectomy to verify the number and distribution of renal vessels. For the entire series, 71 patients had bilateral single, 2 bilateral multiple and 27 multiple renal arteries on one side determined by angiography. Eleven patients required standard catheter angiography due to inadequate IV-DSA studies. Four patients who had a single artery imaged by IV-DSA were found to have an additional vessel at the operation. The overall accuracy of IV-DSA to identify the number of renal vessels was 96% (85/89). The sensitivity of the exam was 100% (94/94) and the specificity was 67% (4/6). It is concluded that IV-DSA combined with excretory urography is a safe, cost effective, and suitable method to image the renal anatomy of potential kidney donors. Thus about 90% of donors can be spared the risks and inconvenience of standard angiography, and the donor evaluation can now be performed on an outpatient basis.

In order to refine the diagnostic possibilities of the radionuclide renal study in transplanted patients and to compensate for the nonspecificity of the 131I-hippuran study in some situation, 99mTc-DTPA WAS USED SIMULTANEOUSLY FOR IMAGING AND TIME-ACTIVITY CURVES. For these curves to be significant, appropriate background subtraction had to be made with a simple computer-processing method. The results obtained have shown that it is possible to distinguish marked acute tubular necrosis from milder degrees, thus affording a prognostic index in the immediate postoperative period, when the hippuran data are often nonspecific. Further, the diagnosis and follow-up of acute rejection episodes can be improved by the DTPA processed curves. Although these curves when examined individually do not show a specific pattern for rejection, they may reveal striking evolutionary changes when compared to the previous studies, even when the hippuran curves are unchanged. The physiologic basis for the differences between the two time-activity curves may be related to the differential handling of the two radiopharmaceuticals by the kidney.

Hyperlipidemia and hypertension, two major risk factors for accelerated atherosclerosis, undoubtedly contribute to the excessive cardiovascular morbidity and mortality experienced by renal transplant recipients. The present survey of posttransplant hyperlipidemia in 500 cyclosporine-treated patients documented a 37.6% incidence of hypercholesterolemia, which occurred within 6 months posttransplant in 82% of patients. An etiologic relation to corticosteroid therapy was suggested by the strong correlation between prednisone doses and cholesterol levels, by the reduced cholesterol levels in patients undergoing steroid withdrawal, and by the reduction in hypercholesterolemia to 13% by 3 years posttransplant when steroid doses were less than 10 mg daily. Hypertriglyceridemia, which was present in 14.7% of the patients, was more severe under CsA-prednisone compared with azathioprine-prednisone therapy. Hypertriglyceridemia, which occurred later in the posttransplant course than hypercholesterolemia, strongly correlated with an excessive percent relative weight and elevated serum creatinine but not with steroid or CsA doses. Increasing age, diabetes mellitus, beta-blockers and nephrotic syndrome contribute to posttransplant hyperlipidemia in the CsA-Pred era as they did in the azathioprine era of immunosuppression.

Although cyclosporine (CsA) displays high immunosuppressive efficacy due to potent selective inhibition of T cell, but not nonspecific, immune functions, the pleiotropic toxicities of the drug result in a low therapeutic index. Thus for a given individual there is at best only a narrow dosage range producing immunosuppression not beclouded by toxicity. Selection of the appropriate CsA dose to achieve this state is complicated by marked inter- and intraindividual variability in drug pharmacokinetics and pharmacodynamics (1). Even considering renal transplant recipients solely, pharmacokinetic variations in drug absorption, volume of distribution, and metabolism as estimated by clearance rates are so great that strategies based on median population values are not useful for a great proportion of patients. Thus it is necessary to devise a CsA strategy that tailors therapy to compensate for interindividual variations. Implementation of such a strategy not only standardizes drug therapy, but also reveals the clinical impact of interindividual differences in the profile of CsA metabolites and in pharmacodynamic effects of a given quantity of CsA, reflecting both the therapeutic actions on the immune system and toxic effects on target organs. Thus a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variation is essential for the eventual dissection of a rational CsA regimen.

Rabbits immunized with the immunoprotective TSTA fraction partially purified by preparative isoelectric focusing of 3 M KCl extracts from a chemically induced murine sarcoma, MCA-F, produced specific xenoantisera as assessed by an indirect membrane immunofluorescence assay. Only the immunizing tumor, MCA-F, and not the antigenically distinct MCA-D or MCA-T target cells were stained by the xenoantiserum. Absorption of anti-MCA-F antiserum with the antigenically distinct MCA-D or MCA-T cells did not reduce its capacity to bind to MCA-F cells. The immunofluorescence reaction was competitively inhibited by MCA-F fractions that induced specific immunoprotection: crude 3 M KCl extract, isoelectrically focused TSTA (fraction 15), and intact irradiated MCA-F cells. The TSTA specificity of these xenoantisera suggests that they may provide useful reagents for rapid isolation and characterization of the immunoprotective moiety.