Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy
| Autor: | Giacomo Basadonna, Andrew I. Lazarovits, David M. Rothstein, Xin Xiao Zheng, Sibrand Poppema, M. Minozzo, N. Kashio, C. Q. Khuong, Lydia Visser, L.A. Auersvald, D. Zekzer, Terry B. Strom, Arjan Diepstra, H. Y. Qian |
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| Rok vydání: | 1998 |
| Předmět: |
Graft Rejection
Male T cell Islets of Langerhans Transplantation Protein tyrosine phosphatase Biology Antibodies Diabetes Mellitus Experimental Mice Transplantation Immunology Immune Tolerance medicine Animals Transplantation Homologous Mice Inbred BALB C geography Multidisciplinary geography.geographical_feature_category Interleukin Biological Sciences Islet medicine.disease Mice Inbred C57BL Transplantation Haematopoiesis medicine.anatomical_structure Immunology Cancer research Leukocyte Common Antigens Immunotherapy Insulitis CD8 |
| Zdroj: | Proceedings of the National Academy of Sciences. 95:3821-3826 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.95.7.3821 |
| Popis: | CD45 is a family of transmembrane protein tyrosine phosphatases exclusively expressed by hematopoietic cells and critically involved in the regulation of T cell activation signals. We now demonstrate that three 100-μg doses of anti-CD45RB mAb MB23G2 can induce long-term engraftment of islets into major histcompatibility complex-disparate chemically diabetic mice. Long-term graft survivors (>120 days) were tolerant to new islet allografts from the original donor strain. MB23G2 induced a temporary decrease in number circulating leukocytes but had no effect on leukocyte number in other lymphoid compartments. Histologic examination of allografts from treated and untreated recipients revealed a similar peri-islet infiltration on day 6. Eleven days after transplant, the peri-islet infiltrate in treated animals persisted, but in marked contrast to untreated control animals, there was no insulitis and islet integrity was preserved. The peri-islet infiltrate from treated animals showed a mild increase in CD4 cells, a decrease in CD8 cells, and decreased intensity of CD45RB expression. Treatment of naive animals with anti-CD45RB (MB23G2) resulted in a shift in CD45 isoform expression on T cells with a loss of higher molecular weight isoforms and increased expression of lower molecular weight (CD45R0) isoform. This shift in CD45 isoform expression from CD45RBHito CD45RBLowas associated with an increase in the intragraft expression of transcripts for interleukin (IL) 4 and IL-10, consistent with the expected activity of this distinct immunoregulatory T cell subset. Antibody-mediated targeting of CD45 may induce tolerance through novel mechanisms and have direct applicability to clinical transplantation in humans. |
| Databáze: | OpenAIRE |
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