Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin.
BACKGROUND
Perioperative lymphocyte depletion induces allograft tolerance in some animal models, but in humans has only been shown to reduce immunosuppressive requirements. Without maintenance immunosuppression, depleted human renal allograft recipients experience rejection characterized by infiltration of the allograft with monocytes and macrophages. T-cell depletion combined with a brief course of deoxyspergualin (DSG), a drug with inhibitory effects on monocytes and macrophages, induces tolerance in nonhuman primates. We therefore performed a trial to determine if lymphocyte depletion with alemtuzumab combined with DSG would induce tolerance in humans.


METHODS
Five recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction. Results were compared to previously studied patients receiving alemtuzumab alone or standard immunosuppression.


RESULTS
Despite profound T-cell depletion and therapeutic DSG dosing, all alemtuzumab/DSG patients developed reversible rejection that was similar in timing, histology, and transcriptional profile to that seen in patients treated with alemtuzumab alone. Chemokine expression was marked prior to and during rejections.


CONCLUSIONS
We conclude that treatment with alemtuzumab and DSG does not induce tolerance in humans. Chemokine production may not be adequately suppressed using this approach.
Kirk
Allan D
AD
Transplantation Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Mannon
Roslyn B
RB
Kleiner
David E
DE
Swanson
John S
JS
Kampen
Robert L
RL
Cendales
Linda K
LK
Elster
Eric A
EA
Wakefield
Terri
T
Chamberlain
Christine
C
Hoffmann
Steven C
SC
Hale
Douglas A
DA
D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003401:Creatine / Q000097:blood; D005260:Female; D006084:Graft Rejection / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000502:physiology; D016030:Kidney Transplantation / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects; D014158:Transcription, Genetic; D023001:Transplantation Tolerance / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D018925:Chemokines; D006146:Guanidines; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D003401:Creatine; C037258:gusperimus