title: Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants.
abstract: Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.
authors.affiliation: 1 Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL. 2 Institute for Cellular Therapeutics, University of Louisville, Louisville, KY. 3 Regenerex, LLC, Louisville, KY.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Leventhal
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Elliott
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bozulic
authors.forename: David J
authors.initials: DJ
authors.lastname: Tollerud
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.forename: Iwona
authors.initials: I
authors.lastname: Konieczna
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ison
authors.forename: John
authors.initials: J
authors.lastname: Galvin
authors.forename: Jayesh
authors.initials: J
authors.lastname: Mehta
authors.forename: Mark D
authors.initials: MD
authors.lastname: Badder
authors.forename: Michael M I
authors.initials: MM
authors.lastname: Abecassis
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002641:Chicago; D003141:Communicable Diseases / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D016867:Immunocompromised Host; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007518:Isoantibodies / Q000097:blood*; D007629:Kentucky; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D023001:Transplantation Tolerance / Q000187:drug effects; D016896:Treatment Outcome; D014611:Vaccination; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies