Ball, ED

Doyle, H

Fontes, P

Fung, JJ

Gupta, P

Kocova, M

McMichael, J

Ricordi, C

Rybka, WB

Starzl, TE

Triulzi, D

Trucco, M

Tzakis, AG

Transplantation Proceedings

English

PubMed

Name not available

Xenotransplantation of hematopoietic cells resistant to HIV as a potential treatment for patients with AIDS

RICORDI, C

TZAKIS, A. G

GUPTA, P

FUNG, J. J

STARZL, T. E

RYBKA, W. B

FONTES, P

BALL, E. D

TRUCCO, M

KOCOVA, M

TRIULZI, D

MCMICHAEL, J

DOYLE, H

University of Miami: Scholarship Miami

D-Scholarship@Pitt

Xenotransplantation of Hematopoietic Cells Resistant to HIV as a Potential Treatment for Patients With AIDS C. Ricordi. A.G. Tzakis. W.B. Rybka. P. Fontes. E.D. Ball. M. Trucco. M. Kocova. D. Triulzi. J. McMichael. H. Doyle. P. Gupta. J.J. Fung. and T.E. Starzl OF THE two types of retroviruses that have been isolated in pallents with acquired Immunodeficiency syndrome (AIDS). human Immunodeficiency Virus-I (H IV -I) is the more common in the United States. Europe. and Central Africa. Very few monkeys have been success-fully infected with HIV -I. including chimpanzee and gib-bon apes. Some of the moculated animals have developed high titer virus-specific antibody responses after infection. However. no ammal has developed the disease. I Gener-ally. small animal species. such as rodents. are even more resistant to AIDS and are not susceptible to HIV infection through nonnal routes. 2 The spread of AIDS and HIV infecllon has become a global concern and the search for" cure has been hampered by the lack of SUitable animal models. We propose to consider these "negallve results" in the development of suitable animal models as a potential clue for the treatment. that is. to verify whether hematopoietic cells from a donor that does not develop AIDS can transfer disease resistance to an infected recipient. If patients with AIDS could be successfully transplanted with xenogeneic bone marrow cells (BMO from a resistant species. a gradual replacement of the dying lymphoid cells of the recipient could occur. with BMC from the resistant donor that could selectively survive. 3 We report the first attempt to verify this hypothesis by reconstitution of an AIDS patient with xenogeneic bone malTow from a resistant species. the baboon. PATIENT AND METHODS The recipient was an HIV-positive. 56-year-old male with ad-vanced AIDS (pancytopema. malnutrition. dehydration. meta-bolic acidosis. chronic CryplOsporidium diarrhea). Lymphocyto-toxicity cross-match was strongly positive (titer 1:2; DTT negative). Cross-matching of patient serum against baboon red blood cells (RBCs) indicated a human antibaboon heteroagglutinin liter of 1:4 (room temperature) and I :32 (Coombs phase). The donor bone marrow was depleted of RBCs resulting in a loss of BMC from 30 x 109 before. to 6.6 x 10" after depletion. The final dose of BMC infused was 0.94 x 1000lkg BMC. comprising 0.48 x 1000lkg CD4- cells. Immunosuppression was with FK-506. Cy-toxan. PGE-I. and steroids. Primers recognizing the chorionic gonadotropin gene of the baboon were used for amplification followed by Southern blot to detect baboon DNA in the recipient at different urnes after transplantauon. H IV titer was measured by quantitauve microcultures performed following senal dilutions PBMC that were co-cultured with I x lOb stimulated normal PBMC. FollOWing culture for 21 days. virus production was measured by p24 assay in culture supernatants. RESULTS AND DISCUSSION Xenogeneic BMC infusion was well tolerated by the pa-lIent and did not produce any early complication such a~ anaphylaxis or graft-versus-host disease. However. nll significant change was observed in circulating CD4 levels. CD4/CDH ratio. and cell-aSSOCiated HIV titer during the follow-up (Table Il. Polymerase chain reaCllon (PCR) results were negative for baboon DNA at 3 to 47 days. The patient was discharged 53 days posttransplant and eventu-ally died 2 weeks later of progressive disease. The results indicated that the baboon BMC failed to engraft. How-ever. xenogeneic BMC infUSIOn did not produce early complicatIOns. Without evidence for xenogeneic BMC engraftment. it was not possible to determine the potenti,,1 of this approach to treat AIDS. We have recent evidence that chimensm can be obtained by BMC xenotransplanta-tion across these species. Two baboons that were treated with a single dose of total lymphoid irradiation (TLI. 750 Gy) before receiving a human bone malTow infusion. were positive for human DNA (PCR) over 6 months following xenotransplantation. The animals did not receive any additional immunosuppressive treatment following the sin-gle dose of TLI (P. Fontes et a!. manuscript in prepara-tion). In addition. we have recently infused baboon bone malTow in a patient who received a liver transplant from the same donorK~ In this case. the baboon bone malTow was not treated to remove RBCs and baboon DNA wa~ detected during the follow-up. indicating that a state of Table 1. PntIrenapiant Day 7 Day 15 Day 28 wec count 3.5 3.6 6.4 5.9 Lymph 210 72 256 1n CD4(%) 2(1) 4(5) 15(6) TFTC CD4ICDB 0.03 0.06 0.1 TFTC HIV titer 4 256 <1 AIlbnMaIlOnS: weC. whne DIOocI cell; HIV. human ImmunoclellCllltlCY YltUS; TFTC. 100 lew to count From the UnIVersity of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address repnnt requests to Dr Camilla Ricordi. UnIVersity of Miami School of MediCine. PO Box 016960 (R-134). Miami. FL 33101. ~ 1994 by Appleton & Lange 004 1 -1345/94/$3.001 + 0 1302 TransplantatIOn ProceedingS. Vol 26. No 3 (June). 1994: pp 1302-1303 fD~ J ~ ' . ...... microchill'leril8t wu eItahIJshod. HOWPW, it oa1IDOC be t.XCIIuded tMt &b. daaoI- IiYw WU IUpOIIliblv fix" tbc ~ c::bbucrk .... bec:aUM it is lOW IaIoWD UIar cldlDeltlmu prat1I& ill RIdpieDU of myorpa~K 4 FIDtber SIIIdieI are aeedecl to detenaine tbe ideal cicaar s:peciu tbII c::auId he used for hem'" ",,!jo!OO recaastitution of padeIa wi1h AIDS. aDd the ideal induction aDdIar immuIIuIuppn:1Ive UUUIIIJM 10 CISlIbllSlla chJmeric Stile in &be recipieDU. REFeRENOES 1. I.ar. HL: JDIIUIIOl Today U:ll2. ISIIIO Z. lrdanvw WJW. WbIJUlD M. J..aU D. LeV)' JA: J Oen Vtml ~Kft1T 3. Jicordi C: Cdl1'rlnlDllllt 2:3. 1m 4. SrarzI TE. DeaIaria AJ. M ... N. al.: .1-..01 Today '4:3:6. J '" 5. SWzl TE. e! II: TdIII1IIIml Prac 26:(dUs isIuc}. )91)4 

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Xenotransplantation of hematopoietic cells resistant to HIV as a potential treatment for patients with AIDS

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