Cellular Immunologie In Vitro Studies of Kidney and Bone
Marrow Transplantation: Cytotoxic Τ Cell Activity—an
Advantage or Disadvantage?
E. Goulmy
T
HE DEVELOPMENT of two cellular
techniques, the mixed lymphocyte
cul-ture' and cell-mediated lympholysis,
2both
now used throughout the world, made it
possi-ble to imitate human organ transplantation
reactions in vitro. Obviously, these assays
reflect only a speeifie aspect of the complex
interactions involved in organ transplantation.
Awareness of the limitations of in vitro
obser-vations is essential when in vivo situations are
to be evaluated. The results of the in vitro
studies presented here must be interpreted
with these restrictions in mind.
The possible clinical relevance of in vitro
analysis of cytotoxic Τ cell (CTL) activity in
renal and bone marrow transplant reeipients
was evaluated.
In kidney transplantation, failure of a
recipient's posttransplantation lymphocytes to
elicit in vitro CTL responses against kidney
donor splenocytes has been shown to correlate
significantly with kidney allograft survival, as
documented in several reports.
3"
6The absence
of host CTL directed speeifieally against the
graft histocompatibility antigens has been
observed not only at the effector cell
popula-tion level. Frequency analyses of alloreactive
CTL percursors (CTL-p) in a group of kidney
reeipients demonstrated a decrease in
donor-speeifie CTL-p frequency after
transplanta-tion, whereas the frequency of irrelevant
third-party donor-reactive CTL-p remained
unchanged.
7Thus, it appears that a marked
decrease in the number of in vitro
donor-directed CTL can eoineide with in vivo graft
tolerance. Functional in vitro clonal deletion
can, however, be compensated by the addition
of exogenous IL2.
8It is likely that this balance
can be disturbcd by activation of the immune
System, for example by viral infection. This
hypothesis is supported by the observations of
Grundy and Shearer,
9who reported that in
certain strains of mice an immunoenhancing
effect of the host immune response to foreign
MHC antigens oecurred during murine
cytomegalovirus infection. Moreover, an
in-crement in the number of IL2 receplor
expressing cells at the peak of inflammation
has also been described.
10It is evident that the State of acquired in
vivo immunologic tolerance as reflected by in
vitro kidney donor-speeifie CTL
nonrespon-siveness is the ulümate goal of transplantation
immunologists. What, however, is the
signifi-cance of this goal? Do the patients who
dis-play long term kidney donor-speeifie CTL
nonresponsiveness suffer a disadvantage? The
increased ineidence of malignant tumors
among organ reeipients, as observed in the
past decade.""
13has been attnbuted to
immu-nosuppressive therapy and its effects, but it
might also be a direct consequence of the State
of acquired tolerance. In support of the latter
hypothesis are experimental findings,
de-scribed previously,8 that showed the presence
of "linked nonresponsiveness" after renal
transplantation: lymphocytes from renal
allo-From the Department of 1 mmunohaematology and The Blood Bank, Leiden University Hospital, The Netherlands
Supported m pari by the Dutch Foundation for Medi-cal and Health Research (Medigonj, the J Α Cohen
Institute for Radiopalhology and Radiation Protection (IRS), the Dutch Kidney Foundation (NSN), Eurotrans-plant, and the Kuratorium für Heimdialyie (KfH)
Address repnnt requeits to Dr t Goulmy, Depart-ment of Immunohaematology, Umveriily Hospital Leid-en, PO Box 9600, 2300 RC LeidLeid-en, The Netherlands
(01988 by Orune ά Stratton, Ine
0041-1345/88/2002-0011 $03 00/0
i
Transplantation Proceedings, Vol XX, No 2 (April), 1988 pp 183-185 183
j
grafled pdttenls with a well functioning grafl display Icidney donor-speuhc CTL nonre-sponsivcness in vitro in addition, these lym-phocytes do not cxhibit a cytolytic response upon Stimulation with ccils from unrclated blood donors sclcctcd for the presence of kid-ney donor HLA Β locus antigens Morcovcr, ccils from panel members matched to the kidney donor at the HI Λ-Β locus but mis-matched at ihc Λ locus suppressed CT1 activ-ily agamst any HLA Α antigen presented on the samc sümulator/targct teil (Tablc I)
Iftolera cc for donor spccihc HLA Β locus ailoantigens is acquired and consequently the "linked no ι-responsiveness" becomes mani-fest, then the Immunologie tolcrance might be much broader lhan anticipaled The biologic rclevance of these phenomena with respect to tumor evolution aftcr rcnal transplantation has still to bc demonstrated
CTi activity tn bone marrow transplanta tion was also investigated and tho chnical relevancc ol in vitro CTI aclivity on the dcvelopmenl ol graft-t-hosl diseasc (GVHD) was evaluated Prcvtously we reported Ihc presence of CTI aclivity in rccipients of an Hl Α genotypieally identical bone marrow graft l 4 As ycl anti host CTL activity o!
posl-transplan' pcnpheral blood lymphocytes (PBl) could bc demonslratt-d mamly (bul not cxclusivuly) in paticnls suflenng from chronic GVHD but not in paticnts without GVHD | S
Sonic of these CTI populalions were subsc quently analy/cd and found to be dirccted against minor histocompalibihly (minor II)
Table 1 Role of Kidney Donor HLA Β Locus Antigens in Posttransplant Cytolytic Nonresponsiveness
Unrelatori 8lood Dot Wth Kidney Donor Arn
Cytolyt c SuppreE Resporut Respoi HLA Β ( t- C) but not Α
HLA Α (+ C) but not Β yes
HLA A f Nono "Posltransplant penphprai blood lymphocytes from CML nonrpsponsive recipients were siimulated in vitro w i t h pither kidney donor HLA Β (and C) or kidney donor HLA Α (dnd C) antigens presented on lymphocytes of jnrelated blood donors
f A n y foretgn HLA Α locus antigen
C GOULMY
antigens requirmg seif HLA class i antigens for recogmtion Analysis at the population level reveaied relatively high phenotype fre-quencies for the minor Η antigens (piovisional designation HA-l to HA-5) identihed Lim ited family studies showcd a Mendclian mode of inhcntance of these anligens The possibie rclevance of minor Η antigens to the dcvelopmcnt of GVHD was invcsligatcd by retrospeetive typing aruilysts ο! Λ serics of HLA-idcnlical bonc marrow donor/recipicnt combinations 1o date, the results of this analysis indicate that incompatibility for onc (or more) minor II antigen between HLA-identical bonc marrow donor and rccipient oecurred prcdominantly in the group of palienls sutTcnng from (chronic) GVHD 15 In
summary the facls that minor Η antigen-specific C l L are gencrated from PBl in patients with chronic GVHD and thal mis matches of onc of the HA antigens oeeur in palicnts who sulier from chronic GVHD not onl> indicate the relalionship between the in vitro obscrvations and the climcally mani fested GVHD, but also supporl the hypolhesis that host-dircclcd minoi Η antigen speufie CTI play a role in the devclopmcnt of GVHD The important question is, of coursc, do these patients beneiit from anlihost CTL activity' The hypothesis that posl bone mar row iransplant antihost CTI aclivity may have a beneficial cHecl is based on ihc assumption that the posiulaled tintileukcmic
polunlial is a desired side efieet of the post bonc marrow transplanl comphcalion GVII
CTL ACTIVITIES IN HUMAN ORGAN TRANSPLANTATION A C K N O W L E D G M E N T
I would likc 10 think 1 1s Blokland and Jos Pool for thcir tcchmeal cxperlisc, Yanda van Rood Anncke Brand, and Jon van Rood for the valuable discussions G Bieger for cditing the tcxl, and Ingrid Curiel for lyping ihe manuscript
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