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K D Chavin

Publications and source records attributed to K D Chavin.

At least 19 recordsLinked to original sources
PubMed2006

Parenchymal transection of the kidney inflicted by endocatch bag entrapment during a laparoscopic donor nephrectomy.

We present a case of inadvertent decapsulation and grade IV renal parenchyma laceration during laparoscopic donor nephrectomy. The kidney was repaired, used and functioned immediately. There were no complications in the donor. To our knowledge, this type of injury has not been reported previously and the purpose of this report is to focus attention on the potential for this unusual injury, which can occur during delivery of the kidney using the endocatch bag.

Adult↗
PubMed2004

Does treatment of cadaveric organ donors with desmopressin increase the likelihood of pancreas graft thrombosis? Results of a preliminary study.

Desmopressin (DDAVP) is commonly used in cadaveric organ donors to treat diabetes insipidus. The thrombogenic potential of DDAVP is well known. Recent animal data have demonstrated that DDAVP impairs pancreas graft (PG) microcirculation and perfusion. The aim of this study was too evaluate the effect of DDAVP on the incidence of PG thrombosis in clinical pancreas transplantation. A retrospective review of simultaneous kidney-pancreas transplant (SKPT) entered in the Scientific Registry of Transplant Recipients (SRTR) between 10/5/87 and 9/27/02 was performed. Patients were included for analysis if there was definitive documentation as to whether DDAVP was (DDAVP-Y) or was not (DDAVP-N) administered to the donor. Both dose and duration of DDAVP treatment were not recorded by SRTR. A total of 2804 SKPTs were available for analysis. Mean follow-up was 1.75 years (range, 1 month to 8.4 years). A total of 1287 SKPT patients (46%) received a PG from a DDAVP-Y donor. Graft ischemia times, donor and recipient ages, recipient gender distribution, surgical techniques, and immunosuppressive regimens were similar in both groups. The overall incidence of PG thrombosis was 4.3%. The incidence of PG thrombosis in recipients of grafts from DDAVP-Y donors was 5.1% compared to 3.5% in recipients of grafts from DDAVP-N donors (P =.04). Fifty-eight percent of thrombosed PG came from DDAVP-Y donors compared to 42% from DDAVP-N donors (P =.04). We conclude that there appears to be a relationship between donor treatment with DDAVP and PG thrombosis. A prospective study is needed to verify these findings and to determine their clinical significance.

Cadaver↗
PubMed2004

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation.

The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.

Creatinine↗
PubMed2004

Valganciclovir prophylaxis in patients at high risk for the development of cytomegalovirus disease.

BACKGROUND: Despite advances in antiviral therapies, cytomegalovirus (CMV) remains the leading opportunistic infection in the transplant population. Valganciclovir (VGC), the L-valyl ester prodrug of ganciclovir (GCV), provides an excellent oral alternative to GCV for the prevention of CMV in transplant recipients. We investigated the use of VGC for CMV prevention in high-risk renal and pancreas transplant recipients. METHODS: Patients at high risk for development of CMV disease were defined as either those who had donor positive, recipient-negative serostatus (D+/R-), or those who received antilymphocyte antibody (ALA) therapy for either rejection treatment or induction. A retrospective review was conducted of all kidney and pancreas transplants performed between August 2001 and December 2003. A total of 341 transplants were performed, of which 109 received VGC, and 88 were included in this analysis. RESULTS: The overall incidence of CMV disease was 5.7% (5/88). All of the CMV episodes were in patients who were D+/R- (17.2% [5/29] versus 0% [0/59], P<0.001). Of these patients, all the episodes of CMV were in patients who received VGC prophylaxis for<100 days post transplant (29% [5/17] versus 0% [0/12], P=0.06). The overall incidence of leukopenia was 11% and thrombocytopenia was 7%, with the incidence between the D+/R- group and the ALA group being similar. CONCLUSION: VGC is an effective agent in preventing CMV disease in kidney and pancreas transplant recipients who are at high risk for developing the disease. The optimal length of prophylaxis in D+/R- patients is still undefined, while 3 months of prophylaxis appears to be sufficient in patients who received ALA therapy.

Adult↗
PubMed2003

Perioperative perfusion strategies for optimal fluid management in liver transplant recipients with renal insufficiency.

Renal Insufficiency (RI) is a common finding in patients suffering from end-stage liver disease. The causes of RI are reported to be multifactorial and the degree of RI can range from early functional impairment to hepatorenal syndrome (HRS). The process of liver transplantation is highly likely to exacerbate the symptoms and sequelae of renal dysfunction. RI continues to be a cause of morbidity and mortality in the intraoperative and postoperative periods. With careful evaluation and monitoring in addition to appropriate intervention, a uniformly good outcome may be possible even for these most complicated patients. This paper will describe successful perfusion interventions carried out during the three phases of liver transplantation: pre-anhepatic, anhepatic and reperfusion at our institution for a three-year period. Intraoperative plasmapheresis (n = 3), continuous veno-venous hemofiltration (CVVH) (n = 7), intraoperative dialysis (n = 8), and intraoperative dialysis with fluid removal (n = 3) techniques will be presented for review.

Adult↗
PubMed2001

Further improvements in laparoscopic donor nephrectomy: decreased pain and accelerated recovery.

Fear of postoperative pain is a disincentive to living donor kidney transplantation. Laparoscopic donor nephrectomy (LDN) was developed in part to dispel this disincentive. The dramatic increase in the number of laparoscopic donor nephrectomies performed at our institution has been in part due to the reduction in postoperative pain as compared to traditional, open donor nephrectomy. We sought to further diminish the pain associated with this surgical technique. The purpose of this study was to compare the efficacy of three different postoperative pain management regimens after LDN. All living kidney donors performed laparoscopically (n=43) between September 1998 and April 2000 were included for analysis. Primary endpoints included postoperative narcotic requirements and length of stay. Narcotic usage was converted to morphine equivalents (ME) for comparison purposes. Patients received one of three pain control regimens (group 1: oral and intravenous narcotics; group II: oral and intravenous narcotics and the On-Q pump delivering a continuous infusion of subfascial bupivicaine 0.5%; and group III: oral and intravenous narcotics and subfascial bupivicaine 0.5% injection). Postoperative intravenous and oral narcotic use as measured in morphine equivalents was significantly less in group III versus groups I and II (group III: 28.7 ME versus group I: 40.2 ME, group II: 44.8 ME; P<0.05). Postoperative length of stay was also shorter for group III (1.8 days) versus group I (2.5 days) and group II (2.9 days). LDN has been shown to be a viable alternative to traditional open donor nephrectomy for living kidney donation. We observed that the use of combined oral and intravenous narcotics alone is associated with greater postoperative narcotic use and increased length of stay compared to either a combined oral and intravenous narcotics plus continuous or single injection subfascial administration of bupivicaine. The progressive modification of our analgesic regimen has resulted in decreased postoperative oral and intravenous narcotic use and a reduction in the length of stay. We recommend subfascial infiltration with bupivicaine to the three laparoscopic sites and the pfannenstiel incision at the conclusion of the procedure to reduce postoperative pain. We believe this improvement in postoperative pain management will continue to make LDN even more appealing to the potential living kidney donor.

Adult↗
PubMed2001

Use of autologous radial artery for revascularization of hepatic artery thrombosis after orthotopic liver transplantation: case report and review of indications and options for urgent hepatic artery reconstruction.

Hepatic artery thrombosis (HAT) is the most common vascular complication after orthotopic liver transplantation (OLT) and has traditionally been managed with re-OLT. However, several reports have shown that urgent revascularization is frequently an effective means of graft salvage. This most often involves hepatic artery (HA) thrombectomy and thrombolysis, with reestablishment of arterial inflow through a donor iliac artery conduit based on the supraceliac or infrarenal aorta. We report a 46-year-old man who developed HAT 13 days after OLT after angiographic splenic artery embolization to reduce splenic artery steal. A suitable donor iliac artery was not available for arterial reconstruction and could not be obtained from neighboring transplant centers. The patient underwent urgent HA thrombectomy, intrahepatic arterial thrombolysis, and revascularization using an autologous radial artery (RA) conduit based on the supraceliac aorta. The patient is alive more than 1 year after revascularization, with normal liver function and documented flow in the arterial conduit by Doppler ultrasound and arteriography. He has not developed late biliary complications or adverse sequelae of RA harvest. Autologous RA can be safely and successfully used as an aortic-based arterial conduit in urgent revascularization of HAT after OLT. RA should be considered for use in HA revascularization if an adequate donor iliac artery is not available and other potential conduits are not usable or desirable. The availability of autologous RA expands the armamentarium of vascular conduits that can be used in HA revascularization and may help minimize re-OLT for otherwise potentially salvageable liver allografts.

Arterial Occlusive Diseases↗
PubMed2001

Endoscopic treatment of post-liver transplantation biliary leaks with stent placement across the leak site.

BACKGROUND: Biliary tract leaks occur in over 10% of patients undergoing liver transplantation and are the most common cause of biliary tract-related death in these patients. A number of treatment options are available, but a standard approach has not been established. METHODS: Twenty-six patients were retrospectively studied who had post-transplantation leaks develop with special reference to those who underwent endoscopic placement of a "leak-bridging" stent. RESULTS: Endoscopic retrograde cholangiography was performed in all cases with no procedure-related complications. Twenty-four patients had a leak-bridging stent, 1 a transpapillary stent, and 1 a nasobiliary drain. Leak resolution occurred in 23 cases (88%) after initial stent placement. The median time to stent removal was 8 weeks. Three patients did not respond to initial treatment; 2 were successfully treated with another stent and a single patient required surgical repair. Four deaths occurred during follow-up, all unrelated to the biliary leak. CONCLUSIONS: Placement of a leak-bridging stent is a safe and effective initial treatment for post-liver transplantation biliary leaks.

Bile↗
PubMed2000

Laparoscopic live donor nephrectomy: the recipient.

BACKGROUND: Laparoscopic live donor nephrectomy offers advantages to the donor in terms of decreased pain and shorter recuperation. Heretofore no detailed analysis of the recipient of laparoscopically procured kidneys has been performed. The purpose of this study was to determine whether laparoscopic donor nephrectomy had any deleterious effect on the recipient. METHODS: A retrospective review was conducted of all live donor renal transplantations performed from January 1995 through April 1998. The control group received kidneys procured via a standard flank approach (Open). Rejection was diagnosed histologically. Creatinine clearance was calculated using the Cockroft-Gault formula. RESULTS: A total of 110 patients received kidneys from laparoscopic (Lap) and 48 from open donors. One-year recipient (100% vs. 97.0%) and graft (93.5% vs. 91.1%) survival rates were similar for the Open and Lap groups, respectively. A similar incidence of vascular thrombosis (3.4% vs. 2.1%, P=NS) and ureteral complications (9.1% vs. 6.3%, P=NS) were seen in the Lap and Open groups, respectively. The incidence of acute rejection for the first month was 30.1% for the Lap group and 31.9% for the Open group (P=NS). The rate of decline of serum creatinine level in the early posttransplantation period was initially greater in the Open group, but by postoperative day 4 no significant difference existed. No difference was observed in allograft function long-term. The median length of hospital stay was 7.0 days for both groups. CONCLUSIONS: Laparoscopic live donor nephrectomy does not adversely effect recipient outcome. The previously demonstrated benefits to the donor, and the increased willingness of individuals to undergo live kidney donation, coupled with the acceptable outcomes experienced by recipients of laparoscopically procured kidneys justifies the continued development and adoption of this operation.

Acute Disease↗
PubMed2000

Outcome in recipients of dual kidney transplants: an analysis of the dual registry patients.

BACKGROUND: A novel but controversial method to increase the utilization of aged donor kidneys is the transplantation of both kidneys as a dual transplant. Initial single-center reports demonstrated outcomes similar to single kidneys from younger donors. In this report, we compare outcome in recipients of kidneys from donors > or =54 years of age who received a single kidney transplant reported to the United Network for Organ Sharing Scientific Registry versus a dual kidney transplant reported to the Dual Kidney Registry. METHODS: A retrospective analysis was performed, comparing four donor and nine recipient and outcome variables between recipients of a single versus a dual transplant between March 1993 and March 1999. RESULTS: Dual versus single transplants from donors > or =54 years of age have a significantly decreased incidence of delayed graft function, and lower serum creatinines up to 2 years after transplant despite having kidneys from significantly older donors with poorer HLA matching. CONCLUSIONS: Dual kidney transplants improve graft performance and outcome in recipients of kidneys from donors > or =54 years of age.

Aged↗
PubMed1999

Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.

Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphorylation and may contribute to obesity through effects on energy metabolism. Because basal metabolic rate is decreased in obesity, UCP2 expression is predicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is increased in genetically obese (ob/ob) mice. In situ hybridization and immunohistochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protein expression are increased in hepatocytes, which do not express UCP2 in lean mice. Mitochondria isolated from ob/ob livers exhibit an increased rate of H+ leak which partially dissipates the mitochondrial membrane potential when the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after transient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regulating UCP2. However, because this decreases the efficiency of energy trapping, the cells become vulnerable to ATP depletion when energy needs increase acutely.

Adenosine Triphosphate↗
PubMed1998

T-cell alterations in cardiac allograft recipients after B7 (CD80 and CD86) blockade.

BACKGROUND: T-cell activation requires engagement of the T cell receptor with the antigen-MHC and simultaneous ligation of the coreceptor CD28. CD28 binds both the CD80 (B7-1) and CD86 (B7-2) ligands on antigen-presenting cells. The functional role of these costimulatory pathways in transplantation is not completely understood. We tested the hypothesis that in vivo blockade of the CD28 pathway via the anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) would prolong allograft survival. METHODS: Neonatal C57BL/6J (H2b) hearts were transplanted to CBA/J (H2k) recipients in a heterotopic nonvascularized model, with anti-CD80 and/or anti-CD86 mAbs being administered intravenously at the time of allografting (day 0) and on the following day (day 1). RESULTS: Anti-CD80 mAb (29.8+/-1.5 days) and anti-CD86 mAb (30.8+/-0.5 days) alone significantly prolonged allograft survival compared with the isotype control (10.7+/-0.4 days, P < 0.01, Wilcoxon rank sum). The concurrent (days 0 and 1) and sequential administration of anti-CD86 mAb on days 0 and 1 plus anti-CD80 mAb on days 2 and 3 prolonged allograft survival to >80 days. Simultaneous administration of anti-CD80 and anti-CD86 mAbs significantly suppressed donor-specific cytotoxic T lymphocyte responses to alloantigen. Anti-CD86 mAb suppressed intragraft interleukin (IL)-4, IL-10, IL-12 p40, and IL-15 mRNA expression. CONCLUSIONS: Anti-CD80 and/or anti-CD86 mAbs are potent immunosuppressants in prolonging allograft survival. Combined blockade of the B7 (CD80 and CD86) ligands seems to be the most effective in prolonging allograft survival and suppressing donor-specific allogeneic cytotoxic T lymphocyte responses. In vivo blockade of CD86, in comparison to CD80, had the greatest immunosuppressive effect on day 7 intragraft cytokines, suggesting its role on early allogeneic immune responses.

Animals↗
PubMed1998

Anti-transferrin receptor monoclonal antibody: a novel immunosuppressant.

BACKGROUND: Transferrin receptor is a widely distributed cell surface receptor present on most proliferating and highly specialized quiescent cells. Expression of transferrin receptor on the surface of immune cells is up-regulated during T-cell activation after the interaction of the antigen-MHC with the T cell receptor. The role of transferrin receptor in T-cell activation has not been well-established. Since transferrin receptor is physically associated with the CD3 zeta-chain, blockade of transferrin receptor has the potential to interfere with the T-cell signals important in transplant rejection. METHODS: Anti-transferrin receptor monoclonal antibody (mAb) was administered in vivo and in vitro to determine whether this agent was effective in prolonging allograft survival and altering cell-mediated immunity. RESULTS: Using donor C57BL/6J (H2b) hearts transplanted to CBA/J (H2k) recipients, anti-transferrin receptor mAb at the time of transplantation prolonged cardiac allograft mean survival time to 25.7+/-0.9 days compared with untreated (13.3+/-0.6 days, P < 0.05) or isotype-matched (10.7+/-0.4 days, P < 0.05) controls. Anti-transferrin receptor mAb administered in vivo failed to suppress the subsequent allogeneic responses. However, when added to culture, anti-transferrin receptor mAb suppressed the allogeneic cytotoxic T lymphocyte response by 79-100% but not the mixed lymphocyte response. CONCLUSIONS: These studies are the first to suggest that transferrin receptor is a potential therapeutic target for clinical transplantation. Future studies will determine the most efficacious dose and time for maximal immunosuppression and the mechanisms responsible for the immunosuppression exhibited by antitransferrin receptor mAb.

Adjuvants, Immunologic↗
PubMed1996

Blockade of multiple costimulatory receptors induces hyporesponsiveness: inhibition of CD2 plus CD28 pathways.

T-lymphocyte activation requires engagement of the T cell receptor with antigen-major histocompatibility complex, and simultaneous ligation of costimulatory pathways via the lymphocyte receptors CD2 and CD28/ CTLA4. Anti-CD2 monoclonal antibody (mAb) blocks the interaction of the antigen-presenting cell receptor CD48 with its ligand CD2, whereas CTLA4Ig binds with high affinity to the antigen-presenting cell ligands B7-1 and B7-2, blocking their interaction with CD28/CTLA4. We tested the immunosuppressive effects of simultaneously blocking both costimulatory pathways. Using donor C57BL/6J (H2b) hearts transplanted to CBA/J (H2k) recipients, anti-CD2 mAb plus CTLA4Ig administered at the time of transplantation prolonged cardiac allograft mean survival time to >120 days compared with untreated controls (12.2+/-0.5 days, P<0.01), anti-CD2 mAb alone (24.8+/-1.0 days, P<0.01), or CTLA4Ig alone (55.0+/-2.0 days, P<0.01). Retransplantation of these recipients with donor-specific and third-party grafts demonstrated that hyporesponsiveness and tolerance were achieved. In vitro stimulation of lymphocytes from tolerant recipients with donor-specific alloantigen resulted in normal cytotoxic T lymphocyte and mixed lymphocyte reaction responses, showing that clonal deletion or anergy did not occur, but that graft adaptation or suppression likely helped to maintain long-term graft survival. In vitro combinations of anti-CD2 mAb and CTLA4Ig suppressed the generation of allogeneic cytotoxic T lymphocytes (58%) and the mixed lymphocyte reaction (36%); CTLA4Ig was more effective in this regard and the two agents were not synergistic. Anti-CD2 mAb and CTLA4Ig suppressed mitogen-driven proliferation in differential fashions, suggesting that they affected independent signaling pathways. Anti-CD2 mAb and CTLA4Ig also inhibited interleukin (IL)-2, IL-4, and IL-2 receptor (CD25). These data indicate that anti-CD2 mAb plus CTLA4Ig induces hyporesponsiveness and tolerance. The mechanism is likely related to the initial disruption of independent pathways of T-lymphocyte activation leading to antigen-specific long-term graft survival.

Abatacept↗
PubMed1996

Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival.

A murine heterotopic, nonvascularized cardiac allograft model was used to examine the effects of the immunosuppressive cytokine, viral IL-10 (vIL-10), delivered by gene transfer on graft rejection. Retroviral-mediated gene transfer and expression of vIL-10 significantly prolonged allograft survival, without conventional systemic immunosuppression, from 12.1 +/- 0.8 days to 39.4 +/- 2.5 days (p < 0.0001). The effect was specific, dose dependent, and restricted to the site of transplantation. PCR analysis demonstrated specific expression of the transferred gene within the allograft. Analysis of the cellular infiltrate in the allografts showed a reduction in T cells and alloantigen-specific cytotoxic T cells and IL-2 producing helper T cells. Thus, the transient local expression of a gene encoding an immunosuppressive protein within a graft can generate local immunosuppression, making gene therapy a viable approach for facilitating transplantation.

Animals↗
PubMed1996

Anti-CD2 monoclonal antibody-induced receptor changes. II. Interaction of CD2 and CD3.

Anti-CD3 monoclonal antibodies (mAbs) and anti-CD2 mAbs each prolong allograft survival and cause transient downmodulation of homologous receptor expression. Anti-CD2 mAbs also act synergistically with anti-CD3 mAbs to prolong allograft survival and induce tolerance. The effect of combined anti-CD2 and anti-CD3 mAb treatment on receptor expression was further analyzed with an in vitro model. The anti-CD2 mAb 12-15 caused CD2 expression on purified splenic T cells to decrease from 72.6% [mean channel fluorescence (MCF) 0.68] to 41.5% (0.45) total positive cells while CD3 expression remained unchanged [69.1% (3.47) to 76.4% (4.04)]. The anti-CD3 mAb 2C11 caused CD2 expression to increase from 72.6% (0.68) to 93.0% (1.74) while CD3 expression decreased from 69.1% (3.47) to 62.6% (2.15). The combination of anti-CD2 plus anti-CD3 preserved CD2 expression (72.6 to 71.1%) while still decreasing CD3 expression [69.1% (3.47) to 69.9% (2.37)]. Modulation of CD2 and CD3 expression was similar on mixed splenic T lymphocytes and isolated CD4 and CD8 subsets. Modulation did not change with the addition of the cytokines IL-1, IL-2, IL-4, IL-6, IL-10, TNF alpha, or TGF beta. Kinetic studies showed that modulation of CD2 was rapid, persistent, and of the same magnitude from Day 1 to Day 7 of culture while CD3 downmodulation was transient. The results of transcriptional analysis and receptor distribution suggested that downmodulation was due to receptor internalization while upmodulation was due to increased transcription. Analysis of expression of other adhesion molecules demonstrated that CD11a, CD18, CD44, CD45, CD48, CD54, and CD62L were significantly increased by either anti-CD2 or anti-CD3 mAbs while the combination was not synergistic. However, anti-CD3 significantly decreased VLA-4 alpha (CD49d) expression and anti-CD2 enhanced this decrease. Conversely anti-CD3 significantly increased IL-2R (CD25) expression and anti-CD2 profoundly inhibited the increase. These results show that anti-CD2 and anti-CD3 mAbs significantly modulate CD2 and CD3 expression on T cells and modulation is accompanied by changes in the array of other T cell surface receptors. Changes in cell surface receptor display may provide an additional explanation for the synergistic effect of anti-CD2 plus anti-CD3 in prolonging allograft survival.

Animals↗
PubMed1995

Anti-CD2 monoclonal antibody-induced receptor changes: down modulation of cell surface CD2.

Anti-CD2 mAbs suppress T cell immunity and prolong allograft survival in vivo while inducing the down-modulation of CD2 expression. Manipulation of cell surface molecules may be important in inducing tolerance, so down-modulation of CD2 expression on T cells by anti-CD2 mAbs was further defined with an in vitro model. The anti-CD2 mAb 12-15 caused CD2 expression on purified splenic T cells to decrease from 83.4 to 22.7% total positive cells while CD3, CD4, and CD8 expression remained unchanged. The expression of other adhesion molecules, LFA-1 alpha (CD11a), LFA-1 beta (CD18), Pgp-1 (CD44), CD45, MEL-14 (L-selectin), and VLA-4 alpha (CD49d), were all increased as a result of anti-CD2 treatment, whereas CD25 (IL-2R), CD48 (CD2 ligand), and ICAM-1 (CD54) remained unchanged. Kinetics showed that CD2 down-modulation was persistent and at the same magnitude from day 1 through day 7 of culture. Anti-CD2 mAb could down modulate CD2 on both CD4 and CD8 splenic lymphocyte subsets, thymocytes, and the T cell lymphoma EL-4; and, non-T cells did not seem to participate in the process of modulation. Mechanistic studies of mAb action showed that, in addition to 12-15, other anti-CD2 mAbs could cause down-modulation of T cell CD2 expression in an epitope and isotype dependent fashion and that CD2 down-modulation correlated with inhibition of receptor-driven T cell stimulation. Intact antibody, including the Fc portion, was required to induce CD2 down-modulation, and additional experiments suggested an interaction with an Fc gamma R other than Fc gamma RII or Fc gamma RIII. CD2 down-modulation did not change with the addition of the cytokines IL-1, IL-2, IL-6, IL-10, TNF alpha, or TGF-beta 1. These results show that anti-CD2 mAbs significantly and persistently down-modulate CD2 on various T cell subpopulations. The mAbs must interact with both the CD2 receptor and an Fc gamma R. CD2 down-modulation is accompanied by changes in the array of other T cell surface receptors that may contribute to mechanisms of anti-CD2-induced immunosuppression.

Animals↗