Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).
BACKGROUND
Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion.


METHODS
Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis.


RESULTS
Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels.


CONCLUSIONS
T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.
Kirk
Allan D
AD
Transplantation and Autoimmunity Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. allank@intra.niddk.nih.gov.
Hale
Douglas A
DA
Mannon
Roslyn B
RB
Kleiner
David E
DE
Hoffmann
Steven C
SC
Kampen
Robert L
RL
Cendales
Linda K
LK
Tadaki
Douglas K
DK
Harlan
David M
DM
Swanson
S John
SJ
D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D044383:Black People; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous; D014481:United States; D044465:White People; D001741:Black or African American
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab