Thymic microchimerism correlates with the outcome of tolerance-inducing protocols for solid organ transplantation.
This study found that pretransplant infusion of donor peripheral blood leukocytes, either total leukocytes (peripheral blood leukocytes) or peripheral blood mononuclear cells (PBMC), under appropriate immunomodulating conditions was more effective than donor bone marrow (BM) in prolonging the survival of rats that received kidney grafts. A higher percentage of MHCII(+) cells was found in donor PBMC than in BM cells, and depletion of MHCII(+) cells from donor PBMC abolished their tolerogenic potential. By the analysis of microchimerism in rats infused with donor cells and killed at different time points thereafter, the better tolerogenic potential of leukocyte infusion related to a higher capability of these cells to engraft the recipient thymus. PCR analysis on OX6-immunopurified cells revealed the presence of donor MHCII(+) cells in the thymus of these animals. The role of intrathymic microchimerism was reinforced by findings that thymectomy at the time of transplant prevented tolerance induction by donor leukocytes. Donor DNA was found in the thymus of most long-term graft animals that survived, but in none of those that rejected their grafts. The presence of intrathymic microchimerism correlated with graft survival, and microchimerism in other tissues was irrelevant. PCR analysis of DNA from thymic cell subpopulations revealed the presence of donor MHCII(+) cells in the thymus of long-term surviving animals. Thus, in rats, donor leukocyte infusion is better than donor BM for inducing graft tolerance, defined by long-term graft survival, donor-specific T cell hyporesponsiveness, and reduced interferon gamma production. This effect appears to occur through migration of donor MHCII(+) cells in the host thymus.
Noris
Marina
M
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Cugini
Daniela
D
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Casiraghi
Federica
F
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Azzollini
Nadia
N
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Moraes
Luciana De Deus Viera
LDV
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Mister
Marilena
M
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Pezzotta
Angela
A
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Cavinato
Regiane Aparecida
RA
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Aiello
Sistiana
S
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Perico
Norberto
N
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Remuzzi
Giuseppe
G
Department of Immunology and Clinics of Organ Transplantation, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D006085:Graft Survival; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D016030:Kidney Transplantation; D007959:Lymphocyte Culture Test, Mixed; D017710:Lymphocyte Transfusion; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000637:transplantation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013934:Thymectomy; D013950:Thymus Gland / Q000502:physiology*; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000949:Histocompatibility Antigens Class II