Combination Therapy of iNKT Cell Ligand and CD40-CD154 Signal Blockade Establishes Islet Allograft Tolerance in Non-Myeloablative Bone Marrow Transplant Recipients.
1Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
2Cluster for Industry Partnerships (CIP), RIKEN, Tokyo, Japan
Meeting: 2017 American Transplant Congress
Abstract number: C270
Keywords: Bone marrow transplantation, Islets, Tolerance
Session Information
Session Name: Poster Session C: Tolerance/Immune Regulation
Session Type: Poster Session
Date: Monday, May 1, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Background: Allogeneic islet transplantation is an effective therapeutic option for type 1 diabetes. Toxicity associated with chronic use of immunosuppressants still remains an obstacle for achieving long-term allograft survival. We previously reported that combination therapy with a liposomal ligand for invariant natural killer T (iNKT) cells (RGI-2001) and an anti-CD154 antibody (MR1) established mixed hematopoietic chimerism and induced donor-specific tolerance. In this study, we attempted to obtain islet graft tolerance using this combination therapy.
Methods: Diabetes was induced in BALB/c mice with streptozocin, followed by bone marrow transplantation (BMT) from C57BL/6 (B6) mice subjected to 3 Gy total body irradiation. We defined the mice receiving combination therapy as tolerant mice and those that did not receive both drugs as rejecters. Three weeks after BMT, approximately 200 islets isolated from B6 mice were transplanted under the kidney capsule. Graft rejection was defined at BS level over 250 mg/dL. Result: All diabetic mice that received the combination therapy developed mixed chimerism. The BS level of tolerant mice decreased after islet transplantation. [figure1] Normoglycemia was maintained until graft removal. Hyperglycemia was not improved in rejecters. Islet allografts were removed 100 days after islet transplantation and hyperglycemia recurred in tolerant mice. Histopathological findings showed no cellular infiltration in islet grafts. Positive insulin staining in the cytoplasm of islet grafts confirmed the graft function. [figure2] In the mixed lymphocyte reaction assay, CD4 and CD8 T cells of tolerant mice showed hypo-responsiveness to donor antigens as well as host antigens.Donor-specific antibody (DSA) was measured by flow cytometry. Molecules of equivalent soluble fluorochrome (MESF) values of DSA in tolerant mice were similar to those in naïve mice.
Conclusion: Combination therapy of RGI-2001 and MR1 establishes islet allograft tolerance in non-myeloablative bone marrow transplant recipients.Our tolerance induction protocol can be used in the future to treat diabetes and improve the prognosis of other organ transplantations.
CITATION INFORMATION: Kanzawa T, Hirai T, Ishii R, Okumi M, Ishida H, Ishii Y, Tanabe K. Combination Therapy of iNKT Cell Ligand and CD40-CD154 Signal Blockade Establishes Islet Allograft Tolerance in Non-Myeloablative Bone Marrow Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Kanzawa T, Hirai T, Ishii R, Okumi M, Ishida H, Ishii Y, Tanabe K. Combination Therapy of iNKT Cell Ligand and CD40-CD154 Signal Blockade Establishes Islet Allograft Tolerance in Non-Myeloablative Bone Marrow Transplant Recipients. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/combination-therapy-of-inkt-cell-ligand-and-cd40-cd154-signal-blockade-establishes-islet-allograft-tolerance-in-non-myeloablative-bone-marrow-transplant-recipients/. Accessed May 25, 2025.« Back to 2017 American Transplant Congress