lJ ')
`II /l
`l!
`VENTH NNUAL MEETING OF THE AMERICAN SOCIETY OF
`!J ] 8 /'-•.
`TRANSPLANT SURGEONS
`"" :..· J
`UN
`CHICAGO, ILLINOIS
`W~tHt.HI ~I i Y OF
`JUNE 5 to 7, 1981
`NGra·~
`OVERVIEW
`•#
`
`Presidential address: role of kidney transplantation and its implementation .
`CERILLI
`
`J .
`
`459
`
`EXPERIMENTAL TRANSPLANT AT ION
`
`Survival of primates following orthotopic cardiac transplantation treated with total
`J. L PENNOCK, B. A.
`lymphoid irradiation and chemical immune suppression.
`REITZ, C. P. BIEBER, S. AZIZ, P. E. OYER, S. STROBER, R. HOPPE, H. S. KAPLAN ,
`E. B. STINSON, AND N. E. SHUMWAY
`Cyclosporin A in experimental lung transplantation. F. J. VEITH, A . J. NORIN, C.
`M . MONTEFUSCO, K. l. PINSKER, S. L KAMHOLZ, M. l . GLIEDMAN, AND E.
`EMESON
`
`CLINICAL TRANSPLANTATION
`
`In situ cadaver kidney perfusion. Experimental and clinical studies. R. T.
`SCHWEIZER, B. A. SUTPHIN, AND S. A. BARTUS
`Human kidney preservation by intracellular electrolyte flush followed by cold storage
`J. M . BARRY, S. LIEBERMAN, C. WICKRE, C. LIEBERMAN, S.
`for over 24 hours.
`FISCHER, AND D. CRAIG .
`Cyclosporin A hepatotoxicity in 66 renal allograft recipients. G. B . G. KLINTMALM ,
`S. IWATSUKI, AND T. E. STARZL
`Method of preservation is not a determinant of graft outcome in kidneys transplanted
`by Southeastern Organ Procurement Foundation Institutions. W . K . VAUGHN,
`G. MENDEZ-PICON, A . L HUMPHRIES, AND E. K. SPEES
`Clinical significance of antimonocyte antibody in kidney transplant recipients. G .
`J. CERILLI, L BRASILE , T. GALOUZIS, AND M. E. DEFRANCIS
`
`467
`
`474
`
`482
`
`485
`
`488
`
`490
`
`495
`Continued on cover 3
`
`PUBLISHED BY THE WILLIAMS & WILKINS CO . BALTIMORE 21202 , U.S.A .
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`tssz
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`PFIZER EX. 1025
`Page 1
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`

`

`Transplantation@
`
`OFFI CIAL JOURNA L OF THE TRANSPLANTATION SOCIETY
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`Royal Postgraduate Medical School
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`Class of 1984
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`PFIZER EX. 1025
`Page 2
`
`

`

`0041-1337/ 81/ 3206-0535$02.00/ 0
`TRANSPLANTATION
`Copyright © 1981 by The Williams & Wilkins Co.
`
`Vol. 32, No.6
`Printed in U.S.A .
`
`TREATMENT OF ACUTE RENAL ALLOGRAFT REJECTION WITH
`OKT3 MONOCLONAL ANTIBODY1
`
`A. BENEDICT COSIMI, ROBERT c. BURTON, ROBERT B . COLVIN, GIDEON GOLDSTEIN,
`FRANCIS L . DELMONico, MICHAEL P. LAQUAGLIA, NINA ToLKOFF-RUBIN, RoBERT H . RuBIN,
`JoHN T. HERRIN, AND PAUL S. RussELL
`
`Transplantation-Immunology Unit of General Surgical Services, Massachusetts General Hospital; Departments of Surgery,
`Pathology, Medicine, and Pediatrics, Harvard Medical School, Boston, Massachusetts; and Ortho Pharmaceutical
`Corporation, Raritan, New J ersey
`
`Eight cadaver donor renal allograft recipients, who
`had received azathioprine and prednisone from the day
`of transplantation, were treated with OKT3 monoclonal
`antibody (reactive with all mature peripheral blood T
`cells) at the time of diagnosis of acute rejection. In all
`cases, loss of essentially all detectable peripheral blood
`OKT3-reactive cells was noted within minutes after the
`initial!- to 5-mg i.v. infusion. Chills and fever invariably
`occurred following the first or second infusion of mono(cid:173)
`clonal antibody, but were not noted during the subse(cid:173)
`quent 10- to 20-day course of therapy, suggesting rapid
`cell lysis as the etiology of this toxicity.
`The established rejection episode was reversed in all
`cases within 2 to 7 days without addition of any therapy
`other than OKT3 antibody and despite continued low(cid:173)
`ering of the steroid dosages. During the subsequent 3- to
`12-month follow-up period, further rejection episodes
`occurred in five of these patients, two of these were
`irreversible with conventional therapy so that six of the
`eight allografts continue with excellent renal function.
`These preliminary observations suggest that homoge(cid:173)
`neity, limited dosage requirements, and ease of in vitro
`monitoring of dosage effects should markedly simplify
`the use of monoclonal antibody to T cell populations in
`human allograft recipients. This second generation of
`antilymphocyte preparations offers the potential for not
`only increased effectiveness but also the possibility of
`manipulating specific T cell subsets.
`
`Although some heterologous antisera to human lymphocytes
`have proved to be effective in delaying or reversing allograft
`rejection (1, 2), the preparation of these agents has been difficult
`using conventional immunization techniques. Even the purified
`IgG fraction from animals immunized with lymphocytes con(cid:173)
`tains not only a heterogeneous group of antibodies to T lym(cid:173)
`phocytes, but also antibodies reactive with other normal cells
`as well as extraneous antibodies reflecting the animal's previous
`immunological activity (3). Therefore, techniques of developing
`more specific reagents have been sought.
`Based upon the recent demonstration by Kohler and Milstein
`(4) that monoclonal antibody to a specific membrane determi(cid:173)
`nant can be reliably produced using cell hybridization tech(cid:173)
`niques, Kung et al. (5) have produced a panel of monoclonal
`antibodies specifically reactive with human lymphocyte sub(cid:173)
`populations. A phylogenetic screen of these reagents in our
`
`1 This work was supported by United States Public Health Service
`Grant HL/ AM-18646 and by funds provided by the Ortho Pharmaceu(cid:173)
`tical Corporation. Presented at the Seventh Annual Scientific Meeting
`of the American Society of Transplant Surgeons, Chicago, Illinois, June
`5 to 7, 1981.
`
`laboratory revealed significant cross-reactivity of some of them
`with lymphocytes of subhuman primates. In order to evaluate
`the possible clinical role of monoclonal antibody as an immuno(cid:173)
`suppressive agent, we previously investigated in cynomolgus
`renal allograft recipients the effects of OKT4 antibody (6). This
`antibody is reactive with human T cells having major helper/
`inducer and T-T collaborative functions (7, 8). By using flow
`cytometry for monitoring of peripheral blood lymphocytes, we
`defined the dosage and timing of OKT4 antibody administration
`required to provide in vivo coating of this specific T cell
`population now in 10 cynomolgus recipients. With a dosage
`range of 0.5 to 1.0 mg/kg/day, coating of all reactive cells was
`observed and residual circulating Ab was usually detectable 24
`hr after administration. When OKT4 therapy was started before
`transplantation, allograft survival was extended to as long as 7
`weeks after a 1- to 2-week course of therapy (control survivalS
`to 11 days).
`Encouraged by the effectiveness, ease of administration, and
`lack of toxicity in this in vivo model, we have begun a trial of
`monoclonal antibody therapy in human renal allograft recipi(cid:173)
`ents. Although the ultimate goal is to evaluate only selected T
`cell subset suppression, in order to expose the patients in this
`initial study to the least risk of ineffective immunosuppression,
`we have tested OKT3 antibody which is reactive with all mature
`human T cells (9, 10).
`
`MATERIALS AND METHODS
`Eight cadaver donor renal recipients, who had received aza(cid:173)
`thioprine and prednisone from the time of transplantation, were
`treated with OKT3 monoclonal antibody at the time of diag(cid:173)
`nosis of acute rejection. Allograft rejection was suggested in
`these patients by deterioration in renal function and was con(cid:173)
`firmed in all patients by histopathological evaluation of tissue
`obtained by percutaneous needle biopsy.
`In the attempt to identify the most effective and least toxic
`combination of conventional and OKT3 therapy, several dosage
`schedules were pursued. In the first two patients, azathioprine
`was administered in a dosage of 10 mg/ kg on the day of
`transplantation and then maintained at 1 to 2 mg/ kg/day unless
`the white blood count fell below 3000/mm3
`• Prednisone was
`begun at a daily dosage of 2 mg/kg. Beginning on the 5th
`postoperative day, the dosage was decreased by 10 mg/ day to
`0.8 mg/kg/day, after which the dosage was more slowly tapered
`to the maintenance dosage of 0.25 mg/ kg/day. Following con(cid:173)
`firmation of the diagnosis of rejection, OKT3 antibody was
`administered by bolus i.v. injection in a total daily dosage of 1
`to 2 mg for 10 days. In the next two patients, the azathioprine
`was reduced to 0.75 mg/ kg/ day and prednisone dosage to 0.6
`
`535
`
`PFIZER EX. 1025
`Page 3
`
`

`

`536
`
`TRANSPLANTATION
`
`Vol. 32, No. 6
`
`R.R.
`C.D. Renal Allograft
`
`mg/kg/day during OKT3 therapy which was administered i.v.
`in a total daily dosage of 1 to 3 mg for 14 days. In the last four
`patients, the azathioprine and prednisone dosages were further
`reduced to 0.4 mg/kg/day during OKT3 therapy. In these
`patients OKT3 was administered daily for 14 to 20 days at a
`dosage of 4 to 5 mg/day (Fig. 1). After discontinuing OKT3
`therapy, the azathioprine dosage was again increased to 1 to 2
`mg/kg/day in the last six patients.
`Prior to transplantation, during azathioprine and prednisone
`therapy, and at frequent intervals after institution of OKT3
`antibody therapy, peripheral blood lymphocytes from huffy
`coat preparations were analyzed for OKT3-reactive cells using
`flow cytometry (lJ). Recipient serum was monitored by incu(cid:173)
`bating sequentially diluted sera with normal human peripheral
`blood lymphocytes, followed by staining with fluoresceinated
`goat anti-mouse antibody, in order to detect and maintain a
`circulating level of OKT3 antibody. Effectiveness of therapy
`was judged by reversal of rejection defined as the day after
`which consistent improvement in renal function occurred. Per(cid:173)
`cutaneous renal biopsies were performed on all patients after
`OKT3 therapy.
`Toxicity was studied by daily monitoring of recipient com(cid:173)
`plete blood count, blood urea nitrogen, and creatinine, weekly
`assays of hepatic function and urine protein excretion, and
`careful observation for any clinical evidence of serum sickness.
`Serial urine, salivary, and huffy coat specimens were cultured
`for viral activity as previously described (12).
`
`RESULTS
`The clinical course of a representative patient treated with
`OKT3 antibody is depicted in Figure 1. Following cadaver
`donor renal transplantation in this 41-year-old male, the serum
`creatinine level fell to normal levels by the 4th post-transplant
`day. Subsequently, the onset of rejection was suggested by the
`rising serum creatinine level which occurred in conjunction
`with decreased urinary output, weight gain, hypertension, and
`low-grade fever. Allograft biopsy confirmed the diagnosis on
`the 7th post-transplant day and the initial 5-mg dose of OKT3
`antibody was infused i.v. after an i.d. skin challenge was ob(cid:173)
`served to produce no reaction. Approximately 45 min later, an
`episode of shaking chills with fever to 101 C occurred. In
`addition, the patient complained of shortness of breath and
`diffuse wheezes were noted over the lung fields. These symp(cid:173)
`toms rapidly responded to acetaminophen and antihistamine
`therapy. The patient had no further chills, fever, or other
`adverse reactions with subsequent OKT3 infusions.
`Sequential monitoring of peripheral blood lymphocytes was
`begun 15 min after the initial injection. As noted in Figure 1,
`there was essentially complete loss of OKT3-reactive cells from
`the peripheral circulation, a condition which persisted through(cid:173)
`out the 14-day course of therapy. That this was not attributable
`to masking or modulation of OKT3 antigen was indicated by
`the failure of fluorescein conjugates of OKT4 and OKT8 mono(cid:173)
`clonal antibodies, which bind to other T cell antigens (JJ) , to
`react with the residual cells. In addition, detectable antibody
`excess was present throughout the course of therapy during
`which a total dosage of 70 mg of OKT3 antibody was adminis(cid:173)
`tered.
`The serum creatinine level continued to rise for several days
`after institution of therapy but the patient's clinical condition
`rapidly improved with diuresis, weight loss, and improved con(cid:173)
`trol of blood pressure being noted within 36 hr of initiation of
`
`0 L ______ _J!!!!!!!!!!!!!!~O~K~T~3~5~m~g~/~d!!ay
`(") ~ (/) ~ 801'.\/'
`I
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`r-f-_J(L
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`/
`rr
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`
`·- ·
`
`•
`
`DAYS POST TRANSPLANT
`FIGURE 1. Clinical course of renal allograft recipient treated for
`acute rejection with OKT3 monoclonal antibody. A dramatic and
`sustained depletion of peripheral blood OKT3-reactive cells and return
`of normal renal function occurred despite rapid tapering of azathioprine
`and steroid dosages.
`
`treatment. Continuous improvement in renal function began 72
`hr after OKT3 treatment was initiated with the serum creati(cid:173)
`nine eventually stabilizing at 1.3 mg/100 ml. As depicted in
`Figure 1, the azathioprine and steroid dosages were rapidlY
`tapered during this period. A second allograft biopsy performed
`on the last day of therapy showed essentially complete resolu(cid:173)
`tion of the histopathological findings of rejection (Fig. 2).
`The initial results of treatment of the eight patients studied
`are• summarized in Tables 1 and 2. In every instance, the
`rejection episode for which OKT3 therapy was instituted was
`reversed with steady improvement in allograft function begin(cid:173)
`ning after 2 to 7 days of therapy. In the frrst three patients and
`the last patient treated, a subsequent rejection episode occurred
`beginning 2 to 6 weeks after cessation of OKT3 therapy while
`the patients were being maintained on azathioprine and pred(cid:173)
`nisone. These episodes were easily reversed in three of these
`patients with increased steroids. The second rejection episode
`in patient 3, however, could not be reversed despite increased
`steroids, local irradiation, and actinomycin D therapy. She
`
`PFIZER EX. 1025
`Page 4
`
`

`

`December, 1981
`
`COSIMI ET AL.
`
`537
`
`returned to dialysis 2 months after transplantation. She subse(cid:173)
`quently developed severe cytomegalovirus infection and expired
`3 months after transplantation.
`Patient 4 is of particular interest because of the development
`during therapy of an antibody response to the OKT3 reagent.
`During the initial 10 days of therapy, peripheral blood T cell
`monitoring of this patient revealed essentially complete loss of
`cells reactive with OKT3 antibody, and allograft function stead(cid:173)
`ily improved from a peak serum creatinine of 8.1 to 2.9 mg/ 100
`ml. During the final 4 days of OKT3 therapy, however, large
`numbers of OKT3-reactive cells were repeatedly demonstrable
`in the patient's peripheral blood and no serum excess of OKT3
`could be achieved even after the dosage of monoclonal antibody
`had been increased from 2 to 5 mg/day. At the time, the steadily
`falling serum creatinine again began to rise and allograft biopsy
`revealed extensive evidence of acute rejection. The immuno(cid:173)
`suppressive protocol was immediately changed to conventional
`therapy with high-dose steroids, local irradiation, and actino(cid:173)
`mycin D; but the rejection process continued, necessitating
`allograft nephrectomy 31 days after transplantation. Evaluation
`of serial serum samples from this patient by flow cytometry
`documented the appearance of anti-OKT3 antibody initially on
`day 10 of therapy with the titer peaking 5 days after therapy
`was discontinued. Characterization of these antibodies will be
`reported in detail elsewhere. No evidence of serum sickness or
`anaphylaxis was noted at any time in this patient.
`Therefore, six of the eight allografts continue with excellent
`renal function 3 to 12 months after OKT3 treatment. All of the
`patients treated with OKT3 antibody developed chills and fever
`
`FIGURE 2. Histopathological picture of renal allograft biopsies be(cid:173)
`fore (left) and after (right) OKT3 monoclonal antibody therapy. Almost
`complete disappearance of the interstitial mononuclear infiltrate and
`reversal of endothelial damage is noted after treatment.
`
`TABLE 1. Cadaver donor renal allograft recipients treated for acute rejection with OKT3 monoclonal antibody
`HLA antigens
`matched
`
`Etiology of renal disease
`
`Age
`
`Sex
`
`Weight
`(kg)
`
`Patient
`
`1
`2
`3
`4
`5
`6
`
`7
`8
`
`16
`52
`59
`41
`41
`39
`
`52
`40
`
`Female
`Male
`Female
`Male
`Male
`Female
`
`Male
`Female
`
`55
`76
`50
`70
`78
`55
`
`56
`51
`
`lgA nephropathy
`Nephrosclerosis
`Interstitial nephritis
`Chronic glomerulonephritis
`Chronic glomerulonephritis
`Dysplasia + focal sclerosing
`glomerulonephritis
`Chronic glomerulonephritis + diabetes
`Polycystic renal disease
`
`0
`
`1
`1
`2
`2
`
`0
`1
`
`" Expired with cytomegalovirus infection after second rejection episode.
`b Maintained on dialysis after loss of allograft during second rejection episode.
`
`TABLE 2. Results of treatment of acute rejection with OKT3 monoclonal antibody
`
`Patient
`
`Post-
`transplant
`day of
`rejection
`
`Prerejection
`creatinine
`(mg/ 100 ml)
`
`Peak
`creatinine
`
`Days to
`reversal
`
`Post-therapy
`creatinine
`
`1
`2
`3
`4
`5
`6
`7
`8
`
`6
`16
`8
`9
`7
`6
`6
`9
`
`1.6
`1.9
`1.6
`5.0
`1.6
`2.9
`3.0
`10.4c
`
`5.4
`4.8
`4.3
`8.1<
`5.8
`8.5
`8.1<
`11.3c
`
`4
`2
`2
`2
`2
`5
`4
`7
`
`1.3
`1.6
`0.9
`2.9
`1.3
`0.9
`1.2
`1.1
`
`T otal OKT3
`
`Mg
`
`13
`20
`18
`34
`70
`57
`90
`100
`
`Days
`
`10
`10
`15
`14
`14
`14
`17
`20
`
`" Reversed with conventional immunosuppression.
`b Irreversible using conventional immunosuppression.
`c On hemodialysis.
`
`Follow-up
`(months)
`
`12
`12
`3"
`8b
`6
`6
`
`4
`3
`
`Subsequent
`rejection
`episode
`
`Yes"
`Yes"
`Yesb
`Yesb
`No
`No
`No
`Yes"
`
`PFIZER EX. 1025
`Page 5
`
`

`

`538
`
`TRANSPLANTATION
`
`Vol. 32, No. 6
`
`to as high as 102 C within 1 hr of the first injection, and several
`were noted to have diffuse wheezing during this period. No
`reactions to subsequent injections were noted and no other
`evidence of toxicity could be identified.
`The effective removal of OKT3-reactive cells (mature T
`lymphocytes) from the circulation within minutes after infusion
`of OKT3 antibody was clearly documented by flow cytometry
`analysis in each case. This dramatic lysis of cells occurred only
`with the first injection, the OKT3-reactive population then
`remaining depressed (except in patient 4) throughout the course
`of therapy.
`
`DISCUSSION
`A central problem in transplantation remains that of incom(cid:173)
`pletely controlled rejection. Intense, nonspecific suppression of
`the recipient's immune system is produced with currently used
`·agents but the level of clinical success and toxicity has changed
`little over the past decade. The only significant addition to this
`regimen has been the gradual acceptance of heterologous anti(cid:173)
`lymphocyte preparations such as antilymphocyte globulin, an(cid:173)
`tithymocyte globulin (ATG), etc. (13), with which a more
`selective suppression of the recipient's cellular immune re(cid:173)
`sponses is anticipated. However, with currently available
`agents, prepared by routine immunization techniques, only 5 to
`10% of the total dose administered represents the actual ther(cid:173)
`apeutic product. As hybridoma technology has developed, the
`possibility of producing anti-T cell monoclonal antibodies with
`effectiveness similar to currently used ATG preparations but
`which are active in much smaller quantities has been realized.
`Furthermore, the feasibility of using antibodies to suppress
`selected T cell subsets rather than the entire population can
`now be tested.
`The results of our studies have begun to delineate the in vivo
`effects of such reagents. We have observed significant immu(cid:173)
`nosuppression in subhuman primate renal allograft recipients
`receiving relatively minute quantities of monoclonal antibody
`(total recipient dosage: 17 to 56 mg compared with 50 to 100
`mg/kg/day (14) when using heterologous ATG preparations).
`Moreover, the OKT4 antibody administered to these recipients
`has been shown to be directed only to the helper/inducer T cell
`subset, reacting with approximately 50 to 60% of human pe(cid:173)
`ripheral blood T cells and 45 ± 9% of cynomolgus T cells. These
`observations demonstrate not only the immunosuppressive po(cid:173)
`tency of monoclonal antibody but also that effective protocols
`may be developed in which the requirement for agents, which
`produce indiscriminate T cell depression, might be markedly
`reduced.
`In our previous clinical evaluation of equine ATG, we have
`found the most definitive means of demonstrating effectiveness
`was in studies in which A TG alone was added to the immuno(cid:173)
`suppressive protocol at the time of diagnosis of acute rejection
`(2). Since only a single agent is being used to reverse a readily
`defmed event, it is possible to elucidate immediately the effect
`of the added therapy without the need for long-term random(cid:173)
`ized trials. Thus, we have pursued a similar model for the
`evaluation of monoclonal antibody. We have selected OKT3
`antibody rather than antibody to a T cell subpopulation in
`order to reduce the likelihood of inadequate suppression in this
`initial trial. Our most important clinical observation in the
`patients treated to date has been the initial reversal in all cases
`of the established rejection episode without addition of any
`therapy other than OKT3 antibody and despite continued
`lowering of the steroid dosage.
`
`Whether improved long-term allograft survival can be
`achieved with such therapy remains to be established; however,
`some observations regarding the addition of monoclonal anti(cid:173)
`body to conventional therapy can be. made. In the fust four
`patients, the attempt was made to 'use the minimum total
`immunosuppression which would produce reversal of the rejec(cid:173)
`tion episode. Thus, the dosage of OKT3 antibody administered
`was limited to that (1 to 2 mg/day) which maintained a barely
`detectable serum antibody level. In each case, except patient 4
`who developed anti-OKT3 antibodies, all clinical manifestations
`of rejection were abolished. However, post-therapy allograft
`biopsies showed persistent cellular infiltration and recurrent
`rejection requiring conventional high-dose steroid therapy ap(cid:173)
`peared within 2 to 6 weeks. All of these patients subsequently
`suffered significant oral infection secondary to herpes simplex
`virus and cytomegalovirus pneumonitis was documented after
`the second rejection episode in two of the patients, one of whom
`subsequently died. These observations appear to emphasize the
`previously proposed concept that a modestly high-dose "net
`state of immunosuppression" over a prolonged period of time is
`probably of greater risk to patients than a limited, more inten(cid:173)
`sive course of therapy (12). In the next four patients, therefore,
`the dosage of OKT3 antibody was sharply increased in an
`attempt to reverse more definitively the rejection activity dur(cid:173)
`ing a limited period of therapy. In addition, as in our studies
`with ATG (14), we have continued to try to limit the dosages of
`azathioprine and prednisone administered during the period in
`which the patients received OKT3 antibody. To date, the
`clinical course in these patients has been much more satisfac(cid:173)
`tory.
`Unacceptable in vivo toxicity of monoclonal antibody admin(cid:173)
`istration has not been observed. The chills, febrile response,
`and occasional wheezing noted on the first day of treatment
`have been found to be readily controlled with antihistamine
`and acetaminophen therapy. These symptoms have been noted
`with ATG treatment as well (15) and have been thought to be
`secondary to release of endogenous pyrogens following exten(cid:173)
`sive lysis of peripheral blood lymphocytes. The observations in
`the patients treated with OKT3 antibody would tend to support
`such an explanation, for the chills and fever were noted only
`after the first infusion concomitant with the dramatic drop in
`the number of circulating T lymphocytes. Subsequent infusions
`were tolerated without similar incidents. It is hoped that later
`morbidity, primarily infection, can be minimized if an appro(cid:173)
`priate dosage of monoclonal antibody can be defined which will
`maximize control of rejection without the addition of other
`agents. It might then be anticipated that long-term morbidity
`would be less than with conventional therapy, since it is gen(cid:173)
`erally accepted that serious complications are most likely to
`occur when large doses of steroids are required to reverse
`rejection activity.
`In copclusion, these observations suggest that the homog~­
`neity, limited dosage requirements, and ease of in vitro moni(cid:173)
`toring of the effects of monoclonal antibody upon T cell popu(cid:173)
`lations in the peripheral blood will simplify their application. to
`patient management. Although, to date, only a reagent reactive
`with all peripheral blood T cells has been evaluated in patients,
`the possibility of manipulating selected T cell subsets is now at
`hand.
`
`LITERATURE CITED
`1. Thomas F, Thomas J , Flora R, Mendez-Picon G, Peace K, Le~
`HM. Effect of antilymphocyte-globulin potency on survival 0
`cadaver renal transplants. Lancet 1977; 2: 671.
`
`PFIZER EX. 1025
`Page 6
`
`

`

`December, 1981
`
`COSIMI ET AL.
`
`539
`
`2. Shield CF, Cosimi AB, Rubin RH, Tolkoff-Rubin NE, Herrin J,
`Russell PS. Use of antithymocyte globulin for reversal of acute
`allograft rejection. Transplantation 1979; 28: 461.
`3. Skamene E, Russell PS. A quantitative study of the binding of ALS
`to various cell types. Clin Exp lmmunol 1971; 8: 195.
`4. Kohler G, Milstein C. Continuous cultures of fused cells secreting
`antibody of predefined specificity. Nature 1975; 256: 495.
`5. Kung PC, Talle MA, DeMaria ME, Butler MS, Lifter J, Goldstein
`G. Strategies for generating monoclonal antibodies defining hu(cid:173)
`man T lymphocyte differentiation antigens. Transplant Proc
`1980; 12: 141.
`6. Cosimi AB, Burton RC, Kung PC, et al. Evaluation in primate
`renal allograft recipients of monoclonal antibody to human T(cid:173)
`cell sub-classes. Transplant Proc 1981; 13: 499.
`7. Reinherz EL, Kung PC, Goldstein G, Schlossman SF. Further
`characterization of the human inducer T cell subset defined by
`monoclonal antibody. J lmmunol 1979; 123: 2894.
`8. Thomas Y, Sosman J , Irigoyen 0, et al. Functional analysis of
`human T cell subsets defmed by monoclonal antibodies. I. Col(cid:173)
`laborative T-T interactions in the immunoregulation of B cell
`differentiation. J lmmunol 1980; 125: 2402.
`9. Kung PC, Goldstein G, Reinherz EL, Schlossman SF. Monoclonal
`
`antibodies defining distinctive human T-cell surface antigens.
`Science 1979; 206: 347.
`10. Chang TW, Kung PC, Gingras SP, Goldstein G. Does OKT3 mono(cid:173)
`clonal antibody react with an antigen-recognition structure on
`human T cells? Proc Natl Acad Sci USA 1981; 78: 1805.
`11. Cosimi AB, Colvin RB, Burton RC, et al. Use of monoclonal
`antibodies to T-cell subsets for immunologic monitoring and
`treatment in recipients of renal allografts. N Engl J Med 1981;
`305:308.
`12. Rubin RH, Cosimi AB, Hirsch MS, et al. Effects of antithymocyte
`globulin on cytomegalovirus in renal transplant recipients. Trans(cid:173)
`plantation 1981; 31: 143.
`13. Cosimi AB. The clinical value of anti-lymphocyte antibodies.
`Transplant Proc 1981; 13: 462.
`14. Cosimi AB, Shield CF, Peters C, Burton R, Scott G, Russell PS.
`Prolongation of allograft survival by cyclosporin A. Surg Forum
`1979; 30: 287.
`15. Cosimi AB, Wortis HH, Delmonico FL, Russell PS. Randomized
`clinical trial of ATG in cadaver renal allograft recipients: Impor(cid:173)
`tance ofT-cell monitoring. Surgery 1976; 80: 155.
`Received 8 June 1981.
`Accepted 10 September 1981.
`
`PFIZER EX. 1025
`Page 7
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