Abstract
CLINICAL OBJECTIVE: To
successfully withdraw immunosuppression in recipients of living-related
donor 1 haplotype matched kidney transplants by treatment with donor
stem cell infusions and Campath-1H (alemtuzumab) anti-CD52 humanized
monoclonal antibody induction to cause a functional state of specific
immunologic tolerance, a significant advance in organ transplant
therapy.
Campath-1H will be
administered intravenously in two doses of 0.3 mg/kg: 1) on the day of
surgery before kidney revascularization, and 2) again four days later.
This regimen will include maintenance tacrolimus (tacro) and
mycophenolate mofetil (MMF) at one-half the usual dosages, but no
corticosteroids. Infusion #1 of donor iliac crest marrow, obtained at
surgery (as in our previous whole marrow infusion protocols), will
then, however, be purified by the Isolex® technology for CD34+ stem
cells, cryopreserved, and administered on post-operative day #5 when
all the Campath-1H targeted lymphoid cell subpopulations will have
reached their nadir. At 4 to 6 months post-operatively, as T and B
cells begin to reappear, tacro will be totally discontinued after
initiation of overlapping therapy with sirolimus (siro) with target
trough levels of 8-15 ng/ml. Infusion #2 of freshly obtained donor stem
cells, mobilized and purified from peripheral blood, will then be
admin-istered. The rationale for this is that, aside from the potent
early Campath-1H lymphoablative effect on the recipient marrow and PBL,
by later substituting sirolimus for tacrolimus, the specific regulatory
effect of co-stimulatory signal blockade by donor stem cell infusion #2
is more likely. However, fewer early acute rejections have been
observed with Campath-1H using (half-dose) tacro and MMF than with
siro; therefore, the plan for the early (4-6 month) half-dose tacro
course.
After 1 year, siro withdrawal
will take place over 6 months if there is no clinical or biopsy
evidence of rejection (Banff Grade 1A or higher). At year 2, again
provided there is no rejection (biopsy), MMF withdrawal will take place
over the next 6 months. Follow-up will be over the ensuing five years.
MECHANISTIC STUDIES:
- We
will use the PCR-Flow assay in peripheral blood monthly, as well as in
iliac crest marrow at 6 months and yearly, to measure donor subset
chimerism in the recipients. A significantly higher percent-age of
multilineage chimerism (of several donor immunohematologic subsets) is
anticipated than in our previously reported series of marrow-infused
recipients, putatively a reflection of donor-specific immunologic
unresponsiveness.
-
The newly developed micro-CML and enzyme-linked ELISPOT assays will be
tested to measure sequential don¬or and recipient chimeric marrow and
peripheral blood immunohematologic cell subset regulatory effects.
-
Yearly kidney biopsies (x4) from the time of surgery, and before,
during, and after immunosuppression withdrawal, will be performed.
Lymphoid cells derived (cultured) from the biopsies will be studied for
chimerism and function.
- To
test for clonal deletion, we will use limiting dilution analysis and
the immunoscope or TcLandscape program, the latter to phenotype and
follow Vbeta family deletion, in collaboration with Dr. Jean-Paul
Soulillou (INSERM, Nantes, France) to take advantage of this ITN Core
laboratory.
Meeting Abstracts
Mathew J, Cirocco R, Rosen A, Vallone T, Gomez C, Blomberg B, Fuller L, Burke GW, Ciancio G, Esquenazi V, Miller J. Tolerogenicity of graft infiltrating lymphocytes in donor stem cell infused kidney transplant recipients treated with alemtuzumab.
ASHI 31st Annual Meeting,
San Diego, CA, October 17, 2006.
[Abstract]
Esquenazi V, Kleiner G, Burke GW, Ciancio G, Ricordi C, Garcia-Morales RO, Cirocco RE, Carreno MR, Kenyon NS, Tzakis AG, Shariatmadar S, Miller J.. Comparative chimerism levels in cadaver and living related donor whole bone marrow infused kidney recipients vs. a 2X stem cell-infused recipient treated with alemtuzumab.
th Basic Science Symposium of the International Transplantation Society,
La Baule, France, June 19-23, 2005.
[Abstract]
Cirocco R, Carreno M, Mathew J, Vallone T, Rosen A, Burke GW, Ciancio G, Esquenazi V, Miller J, Kleiner G. Upregulation of FOXP3 in renal transplantation after antibody induction regimens with and without bone marrow or stem cell infusions.
World Transplant Congress,
Boston, MA, July 22-27, 2006.
[Abstract]
Carreno M, Cirocco R, Mathew J, Ciancio G, Burke GW, Miller J, Esquenazi V.. T regulatory cells after induction therapy with Campath-1H, vs Thymoglobulin vs Daclizumab in kidney transplant recipients.
American Transplant Congress,
Seattle, WA, May 21, 2005.
[Abstract]
Mathew J, Vallone T, Carreno M, Garcia-Morales R, Rosen A, Gomez C, Burke GW, Ciancio G, Esquenazi V, Miller J, Blomberg B, Fuller L. Regulatory cells of donor and recipient phenotypes in donor stem cell infused kidney transplant recipients treated with alemtuzumab.
World Transplant Congress,
Boston, MA, July 22-27, 2006.
[Abstract]
Vallone T, Carreno M, Rosen A, Gomez C, Garcia-Morales R, Blomberg B, Fuller L, Ciancio G, Esquenazi V, Miller J, Mathew JM, Burke G. Regulatory cell development in an LRD-kidney transplant recipient treated with alemtuzumab and donor stem cell infusions (ITN protocol).
ASHI 31st Annual Meeting,
Washington, DC, Oct 17-21, 2005.
[Abstract]
Mathew J, Carreno M, Cirocco R, Rosen A, Vallone T, Garcia-Morales R, Burke GW, Ciancio G, Esquenazi V, Miller J. Circulating and graft infiltrating regulatory cells in donor stem cell infused kidney transplant patients treated with alemtuzumab.
12th Innovative Therapeutics in Transplantation Meeting,
Nantes, France, June 15, 2006.
[Abstract]
Cirocco R, Mathew J, Esquenazi V, Miller J., Careno M, Valone T. Increased production of the regulatory T-cell transcription factor Fox P-3m-RNA and CD4+CD25+ cells in Campath-1H and donor hematopoetic stem cell treated kidney transplant recipients.
ASHI 31st Annual Meeting,
Washington, DC, Oct 17-21, 2005.
[Abstract]
Carreno MR, Ciancio G, Burke GW, Cirocco R, Mathew J, Jin Y, Miller J, Salman F, Esquenazi V.. Precursor dendritic cell subsets in kidney allograft recipients after induction with alemtuzumab (C1H) vs Thymoglobulin (Thy) vs Daclizumab (Dac) vs a C1H recipient given donor specific stem cells (DHSC).
ASHI 31st Annual Meeting,
Washington, DC, Oct 17-21, 2005.
[Abstract]
