Venous drainage of the left liver: an evaluation of anatomical variants and their clinical relevance.

AIM: To evaluate the variations in venous drainage from the left liver. MATERIALS AND METHODS: A retrospective evaluation was performed of all consecutive abdominal computed tomography (CT) examinations at a tertiary referral facility between 1 January and 30 June 2018. Osirix (Pixmeo SARL, Bernex, Switzerland) was used to examine the major hepatic veins and their tributaries in each scan. The classification of variants as proposed by Nakamura and Tsuzuki was used to describe the findings. The following information was collected: ramification pattern, number, length and diameter of middle (MHV) and left (LHV) hepatic vein tributaries. Two researchers collected data independently, and the average measurements were used as the final dimensions. RESULTS: Of 102 examinations evaluated, only 27 demonstrated the conventional venous drainage patterns. The LHV and MHV combined to form a common trunk that emptied into the inferior vena cava (IVC) in 75 (73.5%) cases. The common trunk had a mean length of 8.89 mm and mean diameter of 20.18 mm. Other patterns included Nakamura and Tsuzuki type I (27.5%), type II (29.4%) and type III variants (16.7%). In addition, 4.9% of patients had absent superior middle veins and 80% had supernumerary short hepatic veins (4%). CONCLUSION: Only 26.5% of patients in this population had conventional venous drainage from the left liver. Surgeons and radiologists in hepatobiliary practice should be aware of these variants in order to minimise morbidity when performing invasive procedures.

Propensity score-based analysis of outcomes of laparoscopic versus open liver resection for colorectal metastases.

BACKGROUND: There is a need for high-level evidence regarding the added value of laparoscopic (LLR) compared with open (OLR) liver resection. The aim of this study was to compare the surgical and oncological outcomes of patients with colorectal liver metastases (CRLM) undergoing LLR and OLR using propensity score matching to minimize bias. METHODS: This was a single-centre retrospective study using a prospective database of patients undergoing liver resection for CRLM between August 2004 and April 2015. Co-variates selected for matching included: number and size of lesions, tumour location, extent and number of resections, phase of surgical experience, location and lymph node status of primary tumour, perioperative chemotherapy, unilobar or bilobar disease, synchronous or metachronous disease. Prematching and postmatching analyses were compared. Surgical and oncological outcomes were analysed. RESULTS: Some 176 patients undergoing LLR and 191 having OLR were enrolled. After matching, 133 patients from each group were compared. At prematching analysis, patients in the LLR group showed a longer overall survival (OS) and higher R0 rate than those in the OLR group (P = 0·047 and P = 0·030 respectively). Postmatching analyses failed to confirm these results, showing similar OS and R0 rate between the LLR and OLR group (median OS: 55·2 versus 65·3 months respectively, hazard ratio 0·70 (95 per cent c.i. 0·42 to 1·05; P = 0·082); R0 rate: 92·5 versus 86·5 per cent, P = 0·186). The 5-year OS rate was 62·5 (95 per cent c.i. 45·5 to 71·5) per cent) for OLR and 64·3 (48·2 to 69·5) per cent for LLR. Longer duration of surgery, lower blood loss and morbidity, and shorter postoperative stay were found for LLR on postmatching analysis. CONCLUSION: Propensity score matching showed that LLR for CRLM may provide R0 resection rates and long-term OS comparable to those for OLR, with lower blood loss and morbidity, and shorter postoperative hospital stay.

Total laparoscopic management of lesions involving liver segment 7.

BACKGROUND: Until recently, laparoscopic resection of tumors involving segment 7 (s7) of the liver was seen as a relative contraindication. We analyzed our experiences with laparoscopic resection of tumors in s7. METHODS: Retrospective analysis of prospective database on operative and postoperative characteristics and surgical outcomes of patients in whom the intention was to remove tumors located in s7 of the liver laparoscopically. We defined two groups: those with laparoscopic metastasectomy of s7 (s7 group) and those undergoing laparoscopic right posterior sectionectomy (RPS group). RESULTS: Of 400 patients undergoing laparoscopic liver resection, 20 patients (5 %) underwent total laparoscopic resections of tumors in s7 (7 metastasectomy of s7 and 13 RPS). The type of resection was decided on the basis of tumor size and location. Median age was 70 years (range 46-82), and the indication for surgery was mainly CRLM (n = 13, 65 %) and HCC (n = 4, 20 %). There was 1 (5 %) conversion. Mean operative times were 252 min (±69) for s7 and 271 min (±102) for RPS. The mean intraoperative blood loss was 400 mL (±493) for s7 and 625 mL (±363) for RPS. A Pringle maneuver was used in 86 % of patients in s7 group and 75 % of patients in RPS group. Mean total hospital stay was 4.6 days (±2.5) in s7 and 6.9 days (±7.8) for RPS. The overall R0 resection rate was 95 % (s7 100 %, RPS 92 %). CONCLUSION: Although resection of lesions in s7 is technically demanding, a laparoscopic approach can be performed safely and effectively in experienced hands.

Outcomes of repeat laparoscopic liver resection compared to the primary resection.

BACKGROUND: Repeat laparoscopic liver resection (R-LLR) can be technically challenging. Data on this topic are scarce and many investigators would question its feasibility and outcomes. The aim of the present study was to evaluate the safety, feasibility, oncological efficiency and outcomes of R-LLR. METHODS: We reviewed a prospectively collected database of 403 patients undergoing 422 laparoscopic liver resections (LLRs) from August 2003 to August 2013. Data of 19 patients undergoing R-LLR were analyzed and compared to the primary resection (P-LLR) in these patients. Demographic and clinical data were studied. A subgroup analysis was done for minor resections. RESULTS: Twenty R-LLRs were performed in 19 patients (female 58 %; mean age: 57.5 years; age range: 23-79 years). Colorectal liver metastases (CRLM) were the commonest indication for R-LLR (60 %), followed by neuroendocrine tumor liver metastases (NETLM) (20 %) and hepatocellular carcinoma (HCC) (10 %). The majority (90 %) of resections were for malignant disease (18/20). There were three conversions (15 %), and two patients developed complications (10 %). The operative time (p = 0.005) and blood loss (p = 0.03) were both significantly greater in R-LLR compared to P-LLR, whereas length of stay (median 4 days; p = 0.30) and complications (p = 0.58) did not differ between the groups. R0 resection rates for P-LLR and R-LLR were 95 and 90 %, respectively (p = 0.73). CONCLUSIONS: Repeat LLR is safe, feasible, and can be performed with minimal morbidity. It appears to be technically more challenging than P-LLR, but without any increase in complications or length of hospital stay.

Variants of hepatic arterial supply in a Caribbean population: a computed tomography based study.

AIM: To evaluate the spectrum of hepatic arterial variants in unselected patients undergoing computed tomography (CT) of the abdomen at the main regional referral centre in the northern Anglophone Caribbean. MATERIALS AND METHODS: Two radiologists independently reviewed 309 CT angiographic studies performed over 2 years between 1 July 2010 and 30 June 2012 at a regional hepatobiliary referral centre for the Northern Caribbean. The anatomical variations were described according to a conventional classification proposed by Michels et al. RESULTS: In this Caribbean population, the majority of patients had conventional Michels' type 1 vascular anatomy (63.4%). However, a statistically significantly greater incidence of Michels' type 2 variations (20.4%) were found than that reported in the international literature and a lower incidence of type 3 (5.2%), type 6 (0.6%), and type 9 (0) patterns than previously reported. One case with variations not previously described in this classification was also encountered. CONCLUSION: Although 63.4% of persons in a Caribbean population have conventional vascular anatomy, the distribution of anatomical variants is quite different to that seen in North American and European centres. Interventional radiologists and hepatobiliary surgeons practicing in the Caribbean must be cognizant of these differences in order to minimize morbidity and mortality during invasive procedures.

Hepatic splenosis mimicking HCC in a patient with hepatitis C liver cirrhosis and mildly raised alpha feto protein; the important role of explorative laparoscopy.

BACKGROUND: Splenosis is a heterotropic implantation of splenic fragments onto exposed vascularised peritoneal and intrathoracic surfaces, following splenic injury or elective splenectomy. CASE PRESENTATION: A 60 year old cirrhotic patient was referred to us with a hepatic mass, suspected to be HCC in a cirrhotic liver. A computerized tomography scan (CT) demonstrated a cirrhotic liver with a 2 x 2.7 cm focal hypervascular nodule, lying peripherally at the junction of segment 7 and 8. Diagnostic laparoscopy demonstrated a 3 cm exofitic dark brown splenunculus attached to the diaphragm and indenting the surface of segment 7 of the liver. The lesion was easily resected laparoscopically and shaved from the live surface with no need for a liver resection. The histopathological assessment confirmed the diagnosis of splenunculus, with no evidence of neoplasia. CONCLUSION: Hepatic splenosis is not a rare event and should be suspected in patients with a history of splenic trauma or splenectomy. Correct diagnosis is essential and will determine subsequent management plans. In doubtful cases laparoscopic investigation can offere essential information and should be part of the standard protocol for investigating suspected splenosis.

Laparoscopic left lateral liver sectionectomy: a safe, efficient, reproducible technique.

BACKGROUND: Laparoscopic left lateral sectionectomy (LLLS) is procedure with potential for future transformation into a primarily laparoscopic procedure where surgeons can safely develop laparoscopic experience and gain proficiency. METHODS: Between August 2004 and December 2007, 80 patients underwent laparoscopic liver resections in our unit, 30 of these were left lateral sectionectomies. The indications for surgery were both oncological and non-oncological. RESULTS: 30 LLLS were performed. Median operative time and median postoperative hospital stay group were 180 (40-340) min and 4 (1-6) days, respectively, and were noted to fall significantly between the first (15 patients) and second parts of this series. The median free resection margin was 11 (1.5-30) mm and median perioperative blood loss was 80 (25-800) ml. Two minor complications were observed with no mortality and no conversions to open. CONCLUSION: LLLS is a feasible, safe and efficient procedure, associated with a quick, smooth learning curve. We report our technique illustrating methods and particulars which would be of great help to surgeons developing new laparoscopic liver services.

Surgical resection versus radiofrequency ablation in the treatment of small unifocal hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high worldwide prevalence and mortality. While surgical resection and transplantation offers curative potential, donor availability and patient liver status and comorbidities may disallow either. Interventional radiological techniques such as radiofrequency ablation (RFA) may offer acceptable overall and disease-free survival rates. MATERIALS AND METHODS: Sixty-eight cirrhotic patients matched for age, sex, tumor size, and Child-Pugh grade with small (1-5 cm) unifocal HCC were studied retrospectively to find determinants of overall and disease-free survival in those treated with surgical resection and RFA between 1991 and 2003. RESULTS: Multivariate analysis using Cox proportional regression modeling showed that overall survival was related to tumor recurrence (p = 0.010), tumor diameter (p = 0.002), and treatment modality (p = 0.014); overall p = 0.008. Recurrence was independently related to the use of RFA over surgery (p = 0.023) on multivariate analysis; overall p = 0.034. CONCLUSION: Surgical resection offers longer disease-free survival and potentially longer overall survival than RFA in patients with small unifocal HCC.

Laparoscopic versus open left lateral hepatic sectionectomy: A comparative study.

BACKGROUND: Laparoscopic liver surgery has been difficult to popularize. High volume liver centres have identified left lateral sectionectomy (LLS) as a procedure with potential for transformation into a primarily laparoscopic procedure where surgeons can safely gain proficiency. METHODS: Forty-four patients underwent either laparoscopic (LLLS) or open (OLLS) left lateral sectionectomy (of segments II/III) for focal lesions at Southampton General Hospital. RESULTS: OLLS and LLLS groups were matched for age, sex and tumour types resected. Median operative time in the LLLS group was 180 (40-340) min and 155 (110-330) min in the OLLS group (p=0.885) with median intra-operative blood loss in the LLLS group 80 (25-800) ml versus a larger 470 (100-3000) ml; p=0.002 for patients receiving OLLS. Post-operative stay was also shorter in the LLLS group (3.5 (1-6) days) compared to the OLLS group (7 (3-12) days; p<0.001). Resection margin was not different in the two groups (11 (1.5-30) mm (LLLS) versus 12 (4-40) mm (OLLS); p=1) and neither was the complication rate (13% for LLLS versus 25% for OLLS; p=0.541). There were no conversions to open in the LLLS group and no deaths in either group at 90 days. Between the first and second 12 LLLS the median operative time fell from 240 (70-340) min to 120 (40-120) min; p=0.005 as well as median post-operative hospital stay from 4.5 (2-6) days to 2 (1-4) days, p=0.001. CONCLUSION: LLLS is a viable alternative to OLLS with potential improvements in intra-operative blood loss and shorter hospital stay without adversely affecting successful resection or complication rates. Larger prospective studies are required to explore this new avenue in laparoscopic liver surgery.

Management of a ruptured pseudoaneurysm of common hepatic artery following pancreaticoduodenectomy.

Postoperative pseudoaneurysm formation is one of the most feared complications of pancreatic leak following pancreaticoduodenectomy (PD). Surgical repair may be compromised due to a persistent enzymatic insult on the repaired vessel; therefore, preventive measures should be adopted. We report a case of ruptured hepatic artery pseudoaneurysm occurring 12 days following PD in a patient with a postoperative pancreatic fistula. Emergency surgery revealed that the pseudoaneurysm was situated at the point of surgical transfixation of the gastroduodenal artery. The pseudoaneurysm was successfully managed by under-running of the bleeding point combined with the direct application of hemostatic products to the bleeding surface (TachoSil and Tisseel) to act as a barrier from the pancreatic secretions.

Ruptured left gastric artery aneurysm successfully treated by thrombin injection: case report and literature review.

Aneurysms of the gastric and gastroepiploic arteries account for only about 4% of all splanchnic artery aneurysms. However, rupture is associated with a mortality of up to 70% and usually warrants urgent surgical intervention. We present an interesting case of a patient who presented with haematemasis following rupture of a left gastric artery aneurysm that was successfully treated by percutaneous thrombin injections. A review of the literature for this rare condition is also presented.

Non-operative management of pyogenic liver abscess.

BACKGROUND: Liver abscess is a serious disease traditionally managed by open drainage. The advances in interventional radiology over the last two decades have allowed a change in approach to this condition. We have reviewed our experience in managing liver abscess over the last 7 years. METHODS: Details of all patients admitted with liver abscess between 1995 and 2002 were prospectively entered onto our database. A review was performed to document the use of imaging and drainage techniques. Aetiology, morbidity, mortality and duration of hospital stay were recorded. RESULTS: Forty-two patients (median age 53 [22-85] years; M:F 18:24) were admitted with liver abscess (multiple abscess 20); 19 cases were of portal tract origin, 16 cases were of biliary tract origin and 7 cases were spontaneous. Forty-one patients were managed non-operatively, all received antibiotics (cephalosporins 76%, metronidazole 88%, quinolones 33%). Diagnosis was made on ultrasound scan (22) or CT (20). Five patients were managed with antibiotics alone. Fifteen patients were managed initially with percutaneous aspiration and five subsequently required percutaneous drainage. Twenty-one patients had primary percutaneous drainage, nine requiring a further procedure (aspiration 3, drainage 6). One patient underwent hepatic resection. Median hospital stay was 16 (6-35) days. There was one death, but no procedure-related morbidity. DISCUSSION: Non-operative management of solitary and multiple liver abscesses is safe and effective.

Induction of long-term specific tolerance to allografts in rats by therapy with an anti-CD3-like monoclonal antibody.

Monoclonal antibodies to CD3 have been shown to activate T cells in vivo and in vitro but have also been shown to render T cells anergic in vitro. In this study G4.18, a mouse IgG3 mAb, was produced that appeared to recognize CD3 by its binding to all peripheral T cells, including a population not recognized by mAb to TCR-alpha/beta that was presumed to be TCR-gamma/delta cells. It precipitated molecules in the 24-26 kd region consistent with the CD3 complex as well as molecules approximately 45 and approximately 49 kd that corresponded to TCR alpha and beta chains and a 92-kd complex. Incubating T cells for 24 hr with saturating concentrations of G4.18 caused modulation of the TCR complex. In vitro, it activated T cells but only if prebound to plastic. In solution it inhibited MLC and CML, but not PHA or Con A activation. In vivo, G4.18 was not toxic even in high doses, and this was thought to be due to the inability of this mAb to activate T cells in vitro because the rat lacks Fc receptors for mouse IgG3. Therapy with G4.18 resulted in transient modulation of TCR/CD3 on T cells and depletion of these cells from blood. G4.18 had no depleting effects by lymph node or spleen cells but caused marked, transient thymic involution. Therapy with G4.18 also induced indefinite survival (> 100 days) of PVG (RTIc) heart grafts but not skin grafts in DA (RTIa) hosts. These hosts with long-surviving cardiac transplants, when grafted from PVG skin, accepted these grafts but rejected third-party skin in first-set. Thus G4.18 was shown to induce long-term specific tolerance to an organ allograft.

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. V. Dependence of CD4+ suppressor cells on the presence of alloantigen and cytokines, including interleukin 2.

CD4+ cells from CsA-treated DA rats with long-surviving PVG heart allografts specifically suppress the capacity of naive CD4+ cells to restore allograft rejection in irradiated DA rats, but have normal donor-specific alloreactivity in MLC. CD4+ suppressor cells from CsA-treated DA rats cultured for 3 days against either PVG or DA spleen cells lost the capacity to transfer suppression into irradiated DA rats grafted with PVG hearts and regained the ability to mediate rejection. However, these cells retained suppressor function when stimulated with donor-specific alloantigen in media supplemented with 20% Con A supernatant. CD4+ cells from CsA-treated rats cultured against either third-party stimulator cells or syngeneic cells expressing anti-PVG idiotype in media supplemented with Con A supernatant failed to maintain suppressor cell function. CD4+ cells from CsA-treated rats cultured in media supplemented with Con A supernatant alone also failed to maintain suppressor function. Suppressor cell function in culture was not maintained by rIL-2. mAb to the IL-2 receptor alpha chain (CD25) prevented the maintenance of suppressor cell function in media supplemented with Con A supernatant. Con A supernatant is rich in IFN-gamma, but addition of an anti-IFN-gamma mAb to the culture did not affect the maintenance of suppressor cells. These studies demonstrate that the CD4+ suppressor cell from CsA-treated rats with long-surviving grafts is short-lived; its survival is dependent upon contact with specific alloantigens and cytokines, one of which is IL-2. In the absence of cytokines and/or specific alloantigen, the CD4+ cells regain the capacity to initiate graft rejection in irradiated rats, suggesting that within the CD4+ subpopulation there is a fragile balance between cells with the capacity to suppress and effect rejection.

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. VI. In vitro alloreactivity of T cell subsets from rats with long-surviving allografts.

DA rats treated with a short course of cyclosporine develop specific unresponsiveness to RT1-incompatible PVG donor heart allografts. CD4+ cells, not CD8+ cells, transfer unresponsiveness to irradiated rats. However, host-derived CD8+ cells are important in reestablishing unresponsiveness. In this study, unfractionated lymphoid cells and W3/25+ (CD4+) cells from CsA-treated rats with long-surviving PVG allografts demonstrated normal alloreactivity to PVG alloantigen in the mixed lymphocyte culture and failed to suppress the proliferative response of naive W3/25+ cells to donor-specific alloantigen. MRC OX8+ (CD8+) cells did not proliferate. Sera from CsA-treated rats had no effect on the MLC reactivity of cells from CsA-treated rats, suggesting that blocking or antiidiotypic antibodies did not diminish alloreactivity. IL-2 production by W3/25+ cells from CsA-treated rats was similar to that by W3/25+ cells from naive rats. Specific cytotoxic T cells to PVG were generated in MLC, and the frequency of precursor cytotoxic lymphocytes in CsA-treated rats was similar to that in naive DA rats. In an in vitro assay testing response to idiotype, neither W3/25+ or MRC OX8+ cells from unresponsive rats proliferated. As CD4+ cells from CsA-treated rats lose their capacity to adoptively transfer specific unresponsiveness unless maintained in a cytokine-rich supernatant, all in vitro assays were performed with and without added cytokines, but no change in reactivity consistent with suppression was observed in any assay. CD4+ suppressor cells had no effect on conventional in vitro assays of alloreactivity, preventing the detection of the unresponsiveness in vitro.

Timing and method of reversal of Hartmann's procedure.

The outcome of 145 patients undergoing Hartmann's resection between 1973 and 1989 has been reviewed. The mortality rate of the primary procedure was 8 per cent. Eighty patients proceeded to reanastomosis. Multifactorial analysis of these patients was undertaken to determine the risk involved. The interval between the primary and secondary procedures was found to be the most important factor. Six of 12 patients had clinical evidence of a leak when this interval was < 3 months, compared with seven of 28 for 3-6 months, and none of 40 when the second operation was delayed for > 6 months. All deaths (three patients) and clinical septicaemia (four) occurred in the two 'early' groups. All colovaginal fistulae (three patients) and strictures (three) were associated with stapled anastomoses. No association was found between the complication rate following reanastomosis and the initial pathology or grade of surgeon undertaking the secondary operation.

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. IV. Examination of T cell subsets in graft-versus-host assays.

In DA rats grafted with PVG hearts a short course of cyclosporine induces a state of specific unresponsiveness. In animals with grafts surviving greater than 75 days, the W3/25+ (CD4+) subset loses its capacity to mediate rejection of PVG but not third-party heart grafts when transferred into irradiated DA hosts. In this study we examined whether there was an associated change in the capacity of peripheral lymphoid T cell subsets from unresponsive animals to induce graft versus host (GVH) reactivity. First we demonstrated that there is synergy between naive CD4+ and CD8+ cells in the popliteal lymph node PLN assay, but that alone, only CD4+ and not CD8+ cells proliferate. Unfractionated and CD4+ cells from unresponsive animals produced similar PLN enlargement in both donor-specific (DAxPVG)F1 hosts and third-party (W/FxDA)F1 hosts. This enlargement was comparable to that produced cells from naive and specifically sensitized hosts. MRC OX8+ cells from both unresponsive and naive hosts did not produce PLN enlargement unless large numbers were injected; small numbers of sensitized MRC OX8+ cells produced specific PLN enlargement CD4+ cells from CsA-treated DA did not respond to DA anti-PVG idiotype in an in vivo assay adapted from the host versus graft (HVG) PLN assay. As the PLN assay does not test cells capacity to effect tissue damage, cells from CsA-treated DA rats were tested in a lethal GVHD assay. These cells had the same capacity to induce lethal GVH in irradiated (DAxPVG)F1 and (DAxW/F)F1 hosts. The normal response of cells from unresponsive animals in both proliferative and effector GVH assays shows that cells with the potential to respond to PVG alloantigen and mediate tissue damage are present in unresponsive animals but are prevented from mediating rejection, possibly due to the relatively weak immune stimulus of an organ graft.

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action.

The cellular basis of the specific unresponsiveness that develops in DA rats treated with cyclosporine (CSA) for 10 d after grafting a PVG heart was examined using an adoptive transfer assay. CD4+ cells from rats with long survival grafts specifically lack the capacity to restore PVG heart graft rejection, and can also inhibit the capacity of naive T cells to restore rejection, while in the first few weeks post-transplant, both CD4+ and CD8+ T cells from CSA-treated hosts have the capacity to effect PVG graft rejection. In this study, we demonstrated the CD4+ suppressor cells also had the capacity to inhibit restoration of rejection by CD4+ cells from CSA-treated DA rats recently transplanted with PVG hearts, and from rats sensitized to third party, but not from those specifically sensitized to PVG. They also inhibited the capacity of both naive CD8+ and sensitized CD8+ cells to effect rejection. These results showed that the CD4+ suppressor cell was capable of overriding the capacity to effect rejection of the CD4+ cell and activated CD8+ cells that were present in the CSA-treated host shortly after transplantation. The failure of naive CD8+ cells to augment suppression and the capacity of CD4+ suppressor cells to transfer unresponsiveness to irradiated hosts in which regeneration of CD8+ cells was abolished by thymectomy suggested that it was the CD4+ cell alone that mediated suppression. However, the failure of CD4+ suppressor cells to reinduce unresponsiveness in irradiated hosts whose CD8+ cells had been depleted by therapy with the mAb MRC Ox8 showed that a radioresistant CD8+ cell was required to reestablish the state of specific unresponsiveness. The induction of CD4+ suppressor cells in thymectomized hosts suggested that these cells were derived from long-lived CD4+ lymphocytes. However, their sensitivity to cyclophosphamide and their loss of suppressor function both after removal of the graft and after 3 d in culture demonstrated that the suppressor cell itself had a short lifespan. The CD4+ suppressor was shown to be MRC Ox22+ (CD45R+), MRC Ox17+ (MHC class II), and MRC Ox39+ (CD25, IL-2-R). These studies demonstrated the CD4+ suppressive cell identified in rats with specific unresponsiveness induced by CSA therapy had many features of the suppressor inducer cell identified in in vitro studies of the alloimmune response.(ABSTRACT TRUNCATED AT 400 WORDS)

Cellular basis of allograft rejection in vivo. V. Examination of the mechanisms responsible for the differing efficacy of monoclonal antibody to CD4+ T cell subsets in low- and high-responder rat strains.

MRC OX35, an anti-CD4 mAb, was used to treat high responder Wistar Furth (W/F) (RT1u) and low responder DA (RT1a) rats which had been grafted with directly vascularized hearts from PVG (RT1c) rats across a full MHC plus non-MHC incompatibility. Four doses of mAb at 7 mg/kg given in the first 2 wk postgrafting induced indefinite graft survival (greater than 150 days) in DA hosts, but only delayed rejection to 18 to 42 days in W/F as compared to rejection times of 6 to 8 days in untreated rats. The extension of MRC OX35 treatment to 6 wk in W/F rats induced indefinite graft survival in three of six rats. During treatment MRC OX35 therapy only partially depleted CD4+ cells, and all circulating CD4+ cells were coated with MRC OX35. The capacity of naive CD4+ and CD8+ cells from W/F and DA to be activated to PVG alloantigen was compared both in vitro in an MLC assay and in vivo by an adoptive transfer assay of their capacity to restore rejection of PVG heart grafts in irradiated syngeneic hosts. CD4+ cells from both W/F and DA proliferated in MLC and restored graft rejection. W/F CD8+ cells both proliferated in MLC and restored rejection, but DA CD8+ cells neither proliferated nor reconstituted rejection. Examination of lymphocytes from MRC OX35 treated hosts with long-surviving grafts showed that they were neither depleted of CD4+ T cells nor did they lack the capacity to proliferate to PVG Ag in MLC, this response being similar to that to third-party Ag or by naive lymphocytes. Compared to first-set rejection, PVG skin graft rejection was delayed 2 to 3 days in W/F and 10 to 12 days in DA rats with long-surviving grafts after MRC OX35 therapy, whereas they rejected third-party skin grafts in first-set tempo. These studies show that differences in graft survival in anti-CD4 treated low and high responder strains may be due to the inherent capacity of CD8+ cells to be activated to effect rejection independent of CD4+ cells in W/F but not in DA. In those hosts that accept grafts, there is no evidence of clonal deletion, but there appears to be a form of unresponsiveness akin to that induced in adult rats by other immunosuppressive therapies that protects the graft from rejection.