CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is D... more CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is Dispensable for CD8 T Cell Responses
Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the m... more Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. Recent Findings The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells, has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. Summary A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next-generation CD28 blockers to prevent and reduce alloantibodies over the long term.
Role of accessory cell processing and presentation of shed H-2 alloantigens in allospeci c cytoto... more Role of accessory cell processing and presentation of shed H-2 alloantigens in allospeci c cytotoxic T lymphocyte responses.
4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB... more 4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB ligand (4-1BBL) on APCs. To investigate the role of 4-1BB costimulation for the development of primary immune responses, 4-1BBL-deficient (4-1BBL−/−) mice were infected with lymphocytic choriomeningitis virus (LCMV). 4-1BBL−/− mice were able to generate CTL and eliminate acute LCMV infection with normal kinetics, but CD8 T cell expansion was 2- to 3-fold lower than in wild-type (+/+) mice. In the same mice, virus-specific CD4 Th and B cell responses were minimally affected, indicating that 4-1BB costimulation preferentially affects CD8 T cell responses. This result contrasts with our earlier work with CD40L-deficient (CD40L−/−) mice, in which the CD8 T cell response was unaffected and the CD4 T cell response was markedly impaired. When both 4-1BBL- and B7-dependent signals were absent, CD8 T cell expansion was further reduced, resulting in lower CTL activity and impairing their ability ...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 15, 2018
We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays indiv... more We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays individualized risk estimates of survival and mortality, for the treatment modalities of dialysis versus kidney transplantation. We examined the effect of iChoose Kidney on change in transplant knowledge and access to transplant in a randomized controlled trial among patients presenting for evaluation in three transplant centers. A total of 470 patients were randomized to standard transplantation education (control) or standard education plus iChoose Kidney (intervention). Change in transplant knowledge (primary outcome) among intervention vs. control patients was assessed using 9-items in pre- and post-evaluation surveys. Access to transplant (secondary outcome) was defined as a composite of waitlisting, living donor inquiries, or transplantation. Among 443 patients (n=226 intervention; n=216 control), the mean knowledge scores were 5.1 ± 2.1 pre- and 5.8 ± 1.9 post-evaluation. Change in kno...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 17, 2017
The advent of costimulation blockade provides the prospect for targeted therapy with improved gra... more The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked Fc binding activity and resultant platelet activation. In a non-human primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (MST 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively co...
The widening gap between patients in need of a kidney transplant and the finite number of transpl... more The widening gap between patients in need of a kidney transplant and the finite number of transplantable deceased donor organs resulted in critical review of kidney allocation policy in the USA. The process to reach consensus for change required compromise between arguments for utility and equity. Important amendments to address shortcomings of the old system and projected outcomes of the new system are reviewed. Potential unintended consequences and practical considerations to facilitate implementation of provisions intended to enhance utility and increase access to transplant for population subgroups in the new system are explored. Granular metrics provide built-in flexibility for the new system, making it amenable to modification based on outcomes.
Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroid... more Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroids. Belatacept is a less toxic CNI alternative, but existing regimens rely on steroids and have higher rejection rates. Experimentally, donor bone marrow and sirolimus promote belatacept's efficacy. To investigate a belatacept-based regimen without CNIs or steroids, we transplanted recipients of live donor kidneys using alemtuzumab induction, monthly belatacept and daily sirolimus. Patients were randomized 1:1 to receive unfractionated donor bone marrow. After 1 year, patients were allowed to wean from sirolimus. Patients were followed clinically and with surveillance biopsies. Twenty patients were transplanted, all successfully. Mean creatinine (estimated GFR) was 1.10 AE 0.07 mg/dL (89 AE 3.56 mL/ min) and 1.13 AE 0.07 mg/dL (and 88 AE 3.48 mL/min) at 12 and 36 months, respectively. Excellent results were achieved irrespective of bone marrow infusion. Ten patients elected oral immunosuppressant weaning, seven of whom were maintained rejection-free on monotherapy belatacept. Those failing to wean were successfully maintained on belatacept-based regimens supplemented by oral immunosuppression. Seven patients declined immunosuppressant weaning and three patients were denied weaning for associated medical conditions; all remained rejection-free. Belatacept and sirolimus effectively prevent kidney allograft rejection without CNIs or steroids when used following alemtuzumab induction. Selected, immunologically low-risk patients can be maintained solely on once monthly intravenous belatacept.
The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabete... more The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using antibodies targeting CD154; however, this approach lacks translational potential secondary to associated thromboembolic sequelae. As an alternative strategy targeting the CD40/ CD154 T cell activation pathway, we evaluate the ability of a chimeric anti-CD40 monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into surgically-induced diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and anti-IL-2 receptor (basiliximab), and maintenance therapy with sirolimus and belatacept (a high-affinity CTLA-4Ig variant). Chi220 effectively promoted xenoislet engraftment and survival; five of six treated recipients achieved insulinindependent normoglycemia (mean length of graft survival 90.8 days, maximum survival of 203 days). No thromboembolic phenomena were noted. CD40 represents a promising alternative to CD154 as a therapeutic target in xenoislet transplantation; other potentially translatable anti-CD40 antibodies warrant further investigation in non-human primate models.
Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cel... more Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (␥-irradiation, depletion of the peripheral immune system) or administration of "mega" doses of bone marrow to facilitate reliable engraftment. Although encouraging, many issues remain that may restrict or prevent clinical application of such strategies. We describe an alternative, nonirradiation based strategy using a single dose of busulfan, costimulation blockade, and T cell-depleted donor bone marrow, which promotes titratable macrochimerism and a reshaping of the T cell repertoire. Chimeras exhibit robust donor-specific tolerance, evidenced by acceptance of fully allogeneic skin grafts and failure to generate donorspecific proliferative responses in an in vivo graft-versus-host disease model of alloreactivity. In this model, donor cell infusion and costimulation blockade without busulfan were insufficient for tolerance induction as donor-specific IFN-␥-producing T cells re-emerged and skin grafts were rejected at ϳ100 days. When applied to a murine -thalassemia model, this approach allows for the normalization of hemologic parameters and replacement of the diseased red cell compartment. Such a protocol may allow for clinical application of mixed chimerism strategies in patients with end-stage organ disease or hemoglobinopathies.
CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is D... more CD40-CD40 Ligand Costimulation Is Required for Generating Antiviral CD4 T Cell Responses But Is Dispensable for CD8 T Cell Responses
Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the m... more Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. Recent Findings The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells, has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. Summary A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next-generation CD28 blockers to prevent and reduce alloantibodies over the long term.
Role of accessory cell processing and presentation of shed H-2 alloantigens in allospeci c cytoto... more Role of accessory cell processing and presentation of shed H-2 alloantigens in allospeci c cytotoxic T lymphocyte responses.
4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB... more 4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB ligand (4-1BBL) on APCs. To investigate the role of 4-1BB costimulation for the development of primary immune responses, 4-1BBL-deficient (4-1BBL−/−) mice were infected with lymphocytic choriomeningitis virus (LCMV). 4-1BBL−/− mice were able to generate CTL and eliminate acute LCMV infection with normal kinetics, but CD8 T cell expansion was 2- to 3-fold lower than in wild-type (+/+) mice. In the same mice, virus-specific CD4 Th and B cell responses were minimally affected, indicating that 4-1BB costimulation preferentially affects CD8 T cell responses. This result contrasts with our earlier work with CD40L-deficient (CD40L−/−) mice, in which the CD8 T cell response was unaffected and the CD4 T cell response was markedly impaired. When both 4-1BBL- and B7-dependent signals were absent, CD8 T cell expansion was further reduced, resulting in lower CTL activity and impairing their ability ...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 15, 2018
We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays indiv... more We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays individualized risk estimates of survival and mortality, for the treatment modalities of dialysis versus kidney transplantation. We examined the effect of iChoose Kidney on change in transplant knowledge and access to transplant in a randomized controlled trial among patients presenting for evaluation in three transplant centers. A total of 470 patients were randomized to standard transplantation education (control) or standard education plus iChoose Kidney (intervention). Change in transplant knowledge (primary outcome) among intervention vs. control patients was assessed using 9-items in pre- and post-evaluation surveys. Access to transplant (secondary outcome) was defined as a composite of waitlisting, living donor inquiries, or transplantation. Among 443 patients (n=226 intervention; n=216 control), the mean knowledge scores were 5.1 ± 2.1 pre- and 5.8 ± 1.9 post-evaluation. Change in kno...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 17, 2017
The advent of costimulation blockade provides the prospect for targeted therapy with improved gra... more The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked Fc binding activity and resultant platelet activation. In a non-human primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (MST 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively co...
The widening gap between patients in need of a kidney transplant and the finite number of transpl... more The widening gap between patients in need of a kidney transplant and the finite number of transplantable deceased donor organs resulted in critical review of kidney allocation policy in the USA. The process to reach consensus for change required compromise between arguments for utility and equity. Important amendments to address shortcomings of the old system and projected outcomes of the new system are reviewed. Potential unintended consequences and practical considerations to facilitate implementation of provisions intended to enhance utility and increase access to transplant for population subgroups in the new system are explored. Granular metrics provide built-in flexibility for the new system, making it amenable to modification based on outcomes.
Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroid... more Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroids. Belatacept is a less toxic CNI alternative, but existing regimens rely on steroids and have higher rejection rates. Experimentally, donor bone marrow and sirolimus promote belatacept's efficacy. To investigate a belatacept-based regimen without CNIs or steroids, we transplanted recipients of live donor kidneys using alemtuzumab induction, monthly belatacept and daily sirolimus. Patients were randomized 1:1 to receive unfractionated donor bone marrow. After 1 year, patients were allowed to wean from sirolimus. Patients were followed clinically and with surveillance biopsies. Twenty patients were transplanted, all successfully. Mean creatinine (estimated GFR) was 1.10 AE 0.07 mg/dL (89 AE 3.56 mL/ min) and 1.13 AE 0.07 mg/dL (and 88 AE 3.48 mL/min) at 12 and 36 months, respectively. Excellent results were achieved irrespective of bone marrow infusion. Ten patients elected oral immunosuppressant weaning, seven of whom were maintained rejection-free on monotherapy belatacept. Those failing to wean were successfully maintained on belatacept-based regimens supplemented by oral immunosuppression. Seven patients declined immunosuppressant weaning and three patients were denied weaning for associated medical conditions; all remained rejection-free. Belatacept and sirolimus effectively prevent kidney allograft rejection without CNIs or steroids when used following alemtuzumab induction. Selected, immunologically low-risk patients can be maintained solely on once monthly intravenous belatacept.
The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabete... more The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using antibodies targeting CD154; however, this approach lacks translational potential secondary to associated thromboembolic sequelae. As an alternative strategy targeting the CD40/ CD154 T cell activation pathway, we evaluate the ability of a chimeric anti-CD40 monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into surgically-induced diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and anti-IL-2 receptor (basiliximab), and maintenance therapy with sirolimus and belatacept (a high-affinity CTLA-4Ig variant). Chi220 effectively promoted xenoislet engraftment and survival; five of six treated recipients achieved insulinindependent normoglycemia (mean length of graft survival 90.8 days, maximum survival of 203 days). No thromboembolic phenomena were noted. CD40 represents a promising alternative to CD154 as a therapeutic target in xenoislet transplantation; other potentially translatable anti-CD40 antibodies warrant further investigation in non-human primate models.
Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cel... more Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (␥-irradiation, depletion of the peripheral immune system) or administration of "mega" doses of bone marrow to facilitate reliable engraftment. Although encouraging, many issues remain that may restrict or prevent clinical application of such strategies. We describe an alternative, nonirradiation based strategy using a single dose of busulfan, costimulation blockade, and T cell-depleted donor bone marrow, which promotes titratable macrochimerism and a reshaping of the T cell repertoire. Chimeras exhibit robust donor-specific tolerance, evidenced by acceptance of fully allogeneic skin grafts and failure to generate donorspecific proliferative responses in an in vivo graft-versus-host disease model of alloreactivity. In this model, donor cell infusion and costimulation blockade without busulfan were insufficient for tolerance induction as donor-specific IFN-␥-producing T cells re-emerged and skin grafts were rejected at ϳ100 days. When applied to a murine -thalassemia model, this approach allows for the normalization of hemologic parameters and replacement of the diseased red cell compartment. Such a protocol may allow for clinical application of mixed chimerism strategies in patients with end-stage organ disease or hemoglobinopathies.
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Papers by Thomas Pearson