Immune "tolerance profiles" in donor bone marrow infused kidney transplant patients using multiple ex vivo functional assays.
Ex vivo identification of donor-specific unresponsiveness in organ transplant recipients is important for immunosuppression (IS) minimization. We tested three groups of stable living, related-donor kidney transplant patients up to 11 years postoperatively, i.e., 20 haploidenticals with donor bone marrow cell (DBMC) infusions, eight noninfused haploidentical controls (haplo controls), and 11 HLA-identical controls (HLA-id), using multiple ex vivo immune assays. We observed that no patients developed donor-specific antibodies. The majority showed donor-specific CTL unresponsiveness from year 1 onward. Thirteen of 20 DBMC recipients became specifically donor MLR nonreactive. Depletion of donor cells in DBMC recipients still MLR reactive increased donor-specific reactivity by 75% +/- 36% (p = 0.04). Adding them back in low concentration caused antigen specific inhibition. The frequencies of ELISPOT granzyme-B and interferon-gamma-producing cells somewhat paralleled the CTL and MLR responses. In the trans vivo DTH, 14 of 19 DBMC recipients demonstrated donor-specific unresponsiveness and 16 of 19 showed "linked suppression," vs none of eight and one of eight haplo controls and vs six of 10 and one of 10 HLA-ids, respectively. Most importantly, when all six assays were performed simultaneously, 10 of 18 DBMC, five of 10 HLA-ids, and no haplo controls were specifically donor unresponsive long term. We propose that a cluster analysis combining these assays will reveal tolerant recipients in whom IS minimization may safely be tested. This appears to have occurred in many DBMC-infused recipients.
Department of Surgery and Comprehensive Transplant Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. james-mathew@northwestern.edu
James M
JM
Mathew
Gaetano
G
Ciancio
George W
GW
Burke
Rolando O
RO
Garcia-Morales
Anne
A
Rosen
Edward
E
Wang
Carmen I
CI
Gomez
Bonnie B
BB
Blomberg
Laphalle
L
Fuller
Violet
V
Esquenazi
Camillo
C
Ricordi
Joshua
J
Miller
D000293:Adolescent; D000328:Adult; D000368:Aged; D016026:Bone Marrow Transplantation; D002648:Child; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000175:diagnosis* / Q000276:immunology; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D007371:Interferon-gamma; D053804:Granzymes