S. John Swanson

Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion

T‐cell depletion facilitates reduced immunosuppression following organ transplantation and has been suggested to be pro‐tolerant. However, the characteristics of post‐depletional T cells have not been evaluated as they relate to tolerance induction. We therefore studied patients undergoing profound T‐cell depletion with alemtuzumab or rabbit anti‐thymocyte globulin following renal transplantation, evaluating the phenotype and functional characteristics of their residual cells. Naïve T cells and T cells with potential regulatory function (CD4+CD25+) were not prevalent following aggressive depletion. Rather, post‐depletion T cells were of a single phenotype (CD3+CD4+CD45RA‐CD62L‐CCR7‐) consistent with depletion‐resistant effector memory T cells that expanded in the first month and were uniquely prevalent at the time of rejection. These cells were resistant to steroids, deoxyspergualin or sirolimus in vitro, but were calcineurin‐inhibitor sensitive. These data demonstrate that therapeutic depletion begets a limited population of functional memory‐like T cells that are easily suppressed with certain immunosuppressants, but cannot be considered uniquely pro‐tolerant.

results From A Human Renal Allograft Tolerance Trial Evaluating The Humanized Cd52-specific Monoclonal Antibody Alemtuzumab (campath-1h)

Background. Profound T‐cell depletion before allotransplantation with gradual posttransplant T‐cell repopulation induces a state of donor‐specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath‐1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52‐specific monoclonal antibody that produces profound T‐cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T‐cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T‐cell depletion. Methods. Seven nonsensitized recipients of livingdonor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real‐time polymerase chain reaction‐based transcriptional analysis. Results. Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection‐free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels. Conclusions. T‐cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.

Functionally significant renal allograft rejection is defined by transcriptional criteria

Renal allograft acute cellular rejection (ACR) is a T‐cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T‐cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub‐clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT‐PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up‐regulated during effector TH1 T‐cell activation, most significantly the transcription factor T‐bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy

Renal allograft recipients generally need to take several immunosuppressive agents for life. Calcineurin inhibitors and glucocorticosteroids are the mainstays of most regimens but have undesirable chronic effects. We postulated that aggressive T-cell depletion combined with the newer immunosuppressant sirolimus would permit transplantation without multidrug treatment. We therefore tested T-cell depletion with rabbit antithymocyte globulin followed by sirolimus monotherapy in 12 patients in an open-label study. This approach was tolerated well, and all patients achieved excellent renal function, and most did not need chronic steroid treatment or calcineurin inhibitors. Rejection was typically correlated with low concentrations of sirolimus, indicating continued dependence on maintenance immunosuppression.

Hepatitis C Virus Seropositivity at the Time of Renal Transplantation in the United States: Associated Factors and Patient Survival

National statistics for patient characteristics and survival of renal transplant recipients positive for hepatitis C virus (HCV+) at the time of renal transplant are presented.

Human Immunodeficiency Virus Infection and Kidney Transplantation in the Era of Highly Active Antiretroviral Therapy and Modern Immunosuppression

Before the era of highly active antiretroviral therapy, kidney transplant recipients infected with HIV had increased risk of death compared with HIV-uninfected recipients. More recent single-center reports have indicated improved results, but this has not been assessed in a national population. Therefore, a retrospective cohort study of US adult deceased donor kidney transplant recipients from January 1, 1996, to May 31, 2001 was conducted; patients were followed until October 31, 2001. A total of 27,851 patients had valid recipient HIV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Centers for Medicare and Medicaid Studies Form 2728. Factors independently associated with HIV infection were also assessed by logistic regression analysis. Only 12.8% of HIV-infected recipients were black, compared with 27.6% in the entire study cohort. HIV-infected kidney transplant recipients were significantly less likely to be black in logistic regression analysis (adjusted OR, 0.29; 95% CI, 0.08 to 0.99; P = 0.049), which was the only factor independently associated with HIV infection. It was found that HIV-infected recipients had improved survival compared with HIV-uninfected recipients, although this was not statistically significant in adjusted analysis (adjusted HR, 0.36; 95% CI, 0.05 to 2.53; P = 0.31). Kidney transplantation in HIV-infected patients is plausible and ongoing, but HIV-infected candidates who underwent kidney transplantation in the United States during the course of the study were demographically unrepresentative of HIV-infected candidates generally.

Hepatitis C and Renal Transplantation in the Era of Modern Immunosuppression

Kidneys from donors who are positive for hepatitis C virus (DHCV+) have recently been identified as an independent risk factor for mortality after renal transplantation. However, it has not been determined whether risk persists after adjustment for baseline cardiac comorbidity or applies in the era of modern immunosuppression. Therefore, a historical cohort study was conducted of US adult cadaveric renal transplant recipients from January 1, 1996, to May 31, 2001; followed until October 31, 2001. A total of 36,956 patients had valid donor and recipient HCV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Center for Medicare and Medicaid Studies Form 2728 and previous dialysis access-related complications. It was found that DHCV+ was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P < 0.001), primarily as a result of infection. Mycophenolate mofetil was associated with improved survival in DHCV+ patients, primarily related to fewer infectious deaths. Adjusted analyses limited to recipients who were HCV+, HCV negative, or age 65 and over, or by use of mycophenolate mofetil confirmed that DHCV+ was independently associated with mortality in each subgroup. It is concluded that DHCV+ is independently associated with an increased risk of mortality after renal transplantation adjusted for baseline comorbid conditions in all subgroups. Recipients of DHCV+ organs should be considered at high risk for excessive immunosuppression.

Effect of Donor Factors on Early Graft Survival in Adult Cadaveric Renal Transplantation

Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20 309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from 1 July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/recipient age ratio (≥ 1.10, e.g. a 55‐year‐old donor given to a recipient age 50 years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (CI) 2.36–4.39) and African American donor kidneys (AHR 1.64, 95% CI, 1.24–2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation.

Donor Hepatitis C Seropositivity: Clinical Correlates and Effect on Early Graft and Patient Survival in Adult Cadaveric Kidney Transplantation

The impact of hepatitis C virus-positive donor kidneys on patient survival has not been analyzed in a national study. This study analyzed 20,111 adult (age, > or =16 yr) recipients having solitary cadaveric kidney transplants from adult donors with valid donor hepatitis C serologies from July 1, 1994, to June 30, 1998, in an historical cohort study (the 2000 United States Kidney Data System) of patient survival. Analysis was by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. Of 484 kidneys positive for hepatitis C virus serology, 165 (34%) were given to recipients with confirmed negative hepatitis C serologies. Unadjusted 3-yr patient survival was 93% in all recipients of donor hepatitis C-negative kidneys versus 85% in all recipients of donor hepatitis C-positive kidneys (P = 0.01). Among hepatitis C-positive recipients, those who received hepatitis C-positive kidneys had worse survival than recipients of hepatitis C-negative kidneys. Among elderly hepatitis C-negative recipients, those who received hepatitis C-positive kidneys also had worse survival; in fact, all recipients of donor hepatitis C-positive kidneys had increased risk of mortality (P = 0.028). There were no significant interactions between donor hepatitis C positivity and either recipient hepatitis C positivity or older recipient age. The use of hepatitis C-positive kidneys in recipients who were hepatitis C-negative was fairly common and contrary to some current recommendations. Recipients of donor hepatitis C-positive kidneys were at independently increased risk of mortality, with no evidence that any subgroups were less affected.

Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation.

Background. Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy. Methods. A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually. Results. Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311–911 days), significantly greater than untreated controls (mean survival=7.0 days, P =0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P =0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154. Conclusion. These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.