{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:19:48Z","timestamp":1794007188395,"version":"4.8.0"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19AI131471"],"award-info":[{"award-number":["U19AI131471"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Although common desensitization strategies for patients with broad HLA sensitization permit transplantation\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      transient lowering of donor-specific antibodies, the B cell\u2013response axis from germinal center activation to plasma cell differentiation remains intact. In this study, dual-targeting desensitization with carfilzomib (a proteasome inhibitor) and belatacept (a costimulation blockade agent) prolonged allograft survival in highly sensitized nonhuman primates; it appears to inhibit plasma cells, control the germinal center reaction needed to repopulate this niche, and preserve viral immunity. However, gradual rebound of donor-specific antibodies and antibody-mediated rejection suggests the need to maintain desensitization after transplantation using ongoing suppression of the B cell response. These findings suggest this mechanistic regimen may warrant further examination for translation into human protocols for desensitization, antibody-mediated rejection, and downregulating an established B cell response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Patients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      lowering of donor-specific antibodies, the B cell\u2013response axis from germinal center activation to plasma cell differentiation remains intact.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.05) and bone marrow plasma cells (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Desensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2019030304","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T18:15:13Z","timestamp":1572286513000},"page":"2399-2411","source":"Crossref","is-referenced-by-count":65,"title":["Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients"],"prefix":"10.1681","volume":"30","author":[{"given":"Brian","family":"Ezekian","sequence":"first","affiliation":[{"name":"Department of Surgery, Duke Transplant Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul 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