WEBVTT 00:00.000 --> 00:30.000 position:50% align:top line:0% *This machine-generated transcript may have errors. If remediation or a manually-generated transcript is needed, please contact NLM Support at https://support.nlm.nih.gov.* 00:14.260 --> 00:16.640 a United States Army Medical Department 00:16.640 --> 00:18.880 continuing education program. 00:20.590 --> 00:23.140 Hist o compatibility testing 00:23.820 --> 00:26.650 a panel discussion with dr braun 00:26.940 --> 00:29.530 doctor cell dr gary 00:29.530 --> 00:32.090 boy and dr species 00:34.480 --> 00:36.120 moderated by Roberti. 00:36.120 --> 00:37.760 Lord in lieutenant Colonel U. 00:37.760 --> 00:37.940 S. 00:37.940 --> 00:40.920 Air Force Medical corps assistant chief reno 00:40.920 --> 00:42.600 service Wilford Hall U. 00:42.600 --> 00:42.780 S. 00:42.780 --> 00:45.550 Air Force Medical Center Lackland Air Force Base. 00:46.920 --> 00:48.980 We have several good questions that have been 00:49.840 --> 00:52.080 sent up here and having quickly glanced at them. 00:52.080 --> 00:54.670 I don't have the answers to all of them will begin 00:54.670 --> 00:55.420 by. 00:55.430 --> 00:57.600 Although this wasn't specifically directed all 00:57.840 --> 01:00.240 direct this to dr braun 01:01.260 --> 01:01.790 dr brown. 01:01.790 --> 01:04.550 Would you use a one haplotype living related donor with a 01:04.550 --> 01:06.130 mildly abnormal M. 01:06.130 --> 01:06.330 L. 01:06.330 --> 01:06.750 C. 01:08.490 --> 01:11.090 A mildly abnormal 01:11.090 --> 01:11.950 mlc. 01:12.070 --> 01:15.070 Well we've used a lot of one haplotype 01:15.070 --> 01:17.990 identical uh transplants 01:17.990 --> 01:18.710 living related. 01:19.040 --> 01:20.960 I still feel that the 01:22.660 --> 01:25.360 there are significant advantages in using living related 01:25.370 --> 01:28.220 donors and looking at serial renal blood flows in 01:28.220 --> 01:29.250 these combinations. 01:29.750 --> 01:32.720 It usually turns out that if you use a living 01:32.720 --> 01:35.010 related Sibling even 01:35.010 --> 01:38.000 mismatched that you've got enough of a renal blood 01:38.000 --> 01:38.640 flow buffer. 01:38.640 --> 01:41.470 That even if they go through an annual rejection and we've 01:41.470 --> 01:44.440 seen two of these you can get them through with a functioning 01:44.440 --> 01:45.050 graph. 01:45.060 --> 01:47.530 Pulling them out with serum creatinine of less than 01:47.540 --> 01:50.290 two and still have about 400 mils of 01:50.300 --> 01:52.800 blood flow left to work on. 01:52.940 --> 01:55.450 So they can tolerate a serious 01:55.450 --> 01:58.390 rejection much better than a cadaver graft will 01:58.400 --> 02:01.280 where you might start out with 400 mils of blood flow. 02:01.280 --> 02:04.190 And after they get belted with a serious rejection 02:04.220 --> 02:06.900 they've got 200 their creatinine is 10 02:07.000 --> 02:09.060 and you can't keep them off dialysis. 02:09.070 --> 02:11.750 So I think there's enough of a 02:11.760 --> 02:14.590 physiologic buffer in there that you can tolerate 02:14.600 --> 02:17.300 a serious rejection in a single haplotype 02:17.310 --> 02:19.280 sibling transplant that you can't 02:19.630 --> 02:21.400 tolerate in a cadaver graft. 02:21.410 --> 02:24.370 Now that's not a an immunological answer or based 02:24.370 --> 02:25.020 on typing, 02:25.020 --> 02:27.010 which is what the question was aimed at. 02:27.020 --> 02:29.940 But I think it's a practical approach 02:29.940 --> 02:30.360 to these. 02:30.360 --> 02:33.150 And we've looked at some of our living related 02:33.160 --> 02:36.120 graphs now who have been functioning for 10 years and 02:36.120 --> 02:37.330 they are mismatched, 02:37.690 --> 02:39.930 living related in some cases and 02:39.940 --> 02:42.750 unmatched cadavers so that they 02:42.750 --> 02:45.650 certainly have the potential for long term 02:45.650 --> 02:46.430 survival. 02:47.030 --> 02:49.840 And the fact of the matter is that we 02:49.840 --> 02:51.820 still don't have ways of 02:51.830 --> 02:54.830 evaluating the ability of 02:54.830 --> 02:57.030 a recipient to tolerate a graft. 02:57.040 --> 02:59.730 We still are unsure really of what the 02:59.730 --> 03:02.650 significance of blocking factors are beforehand and we still 03:02.650 --> 03:05.450 don't know how to evaluate the presence or absence 03:05.460 --> 03:07.950 of suppressor cells in these situations. 03:07.960 --> 03:09.830 But I certainly would 03:10.690 --> 03:13.470 preferentially go ahead with a living related 03:13.470 --> 03:16.240 single appetite mismatched sibling transplant 03:16.570 --> 03:19.260 from a young age group in preference 03:19.260 --> 03:21.580 to a cadaver waiting list. 03:23.690 --> 03:26.470 There are two questions that uh are 03:26.470 --> 03:27.180 quite interesting. 03:27.190 --> 03:28.340 The first is, 03:28.340 --> 03:30.880 what is the current status of our liberal transfusion 03:30.880 --> 03:33.690 regimen to identify non 03:33.700 --> 03:36.660 and or hyper responders or I think what they 03:36.660 --> 03:39.630 mean is people who do not form antibodies when sensitized versus 03:39.630 --> 03:42.430 people who form a lot of antibodies are sensitized 03:42.440 --> 03:45.410 and a very similar question is do you think 03:46.150 --> 03:48.890 pre sensitization might be useful because it would 03:48.890 --> 03:51.390 identify people who are quote hyper 03:51.390 --> 03:54.140 responders and should be and should transfusions 03:54.150 --> 03:54.520 uh, 03:54.530 --> 03:57.060 and I presume they mean transfusions of whole blood be 03:57.060 --> 03:57.840 restarted? 03:58.670 --> 03:58.980 Well, 03:58.980 --> 04:01.730 I'll ask several people on the panel to comment on that. 04:01.730 --> 04:03.010 And I'll begin with myself. 04:04.680 --> 04:07.570 We have had several instances in our 04:07.580 --> 04:10.050 own transplant program where people did not have 04:10.050 --> 04:12.490 identifiable or known or at least 04:12.500 --> 04:14.580 willing living related 04:14.590 --> 04:17.360 individuals uh for purposes of giving 04:17.360 --> 04:18.960 them a kidney. 04:19.000 --> 04:21.920 And these people have been put on the cadaver list and 04:21.920 --> 04:24.690 over a period of time have received 04:24.690 --> 04:27.160 transfusions in the course of a chronic dialysis 04:27.160 --> 04:27.720 regimen. 04:28.090 --> 04:31.010 And then lo and behold up comes a missing 04:31.010 --> 04:33.960 brother or absent father who indeed 04:33.960 --> 04:36.380 suddenly has realized that a 04:36.390 --> 04:39.360 transplant for the particular patient in hand would 04:39.360 --> 04:40.710 be useful and is willing to do it. 04:40.720 --> 04:43.500 And we find that we've sensitized this individual to the living 04:43.500 --> 04:44.350 related person. 04:45.310 --> 04:47.790 So you've eliminated that person and from potentially being 04:47.790 --> 04:49.630 transplanted with a living related graft, 04:49.990 --> 04:52.690 which is far superior in my mind under any 04:52.690 --> 04:54.720 circumstances than any cadaver graft. 04:54.730 --> 04:55.290 So, 04:55.290 --> 04:56.710 for that reason alone, 04:58.180 --> 05:00.900 I don't feel we should liberally transfuse anybody in the 05:00.900 --> 05:01.260 fact, 05:01.270 --> 05:03.560 even if they are responders, 05:03.560 --> 05:06.560 we may at least prevent them from being sensitized 05:06.560 --> 05:09.220 against a given individual who they're related to 05:10.100 --> 05:12.940 whether or not it's useful to know if someone has 05:13.850 --> 05:16.360 the capacity to form antibodies or not to form antibody 05:17.740 --> 05:20.530 is as I tried to indicate when I in my talk 05:21.340 --> 05:24.000 a matter of opinion and clearly not settled 05:25.010 --> 05:27.930 I think that if someone has the 05:27.930 --> 05:29.410 capacity to form antibodies 05:31.150 --> 05:32.780 and they've never been sensitized 05:34.030 --> 05:37.020 the capacity of form and a body is obviously still there when 05:37.020 --> 05:39.190 they are first sensitized say by a kidney 05:39.190 --> 05:40.120 graft. 05:40.190 --> 05:42.940 And it may well indeed although not 05:42.950 --> 05:44.910 clearly shown it may well indeed make this 05:44.910 --> 05:47.560 individual less likely to 05:47.570 --> 05:50.490 have a graft survival compared to someone who 05:50.490 --> 05:51.850 doesn't have this capacity. 05:55.470 --> 05:57.970 It may indeed be 05:57.980 --> 06:00.860 possible that if this individual response 06:00.870 --> 06:03.810 is a responder or forms antibody that 06:03.810 --> 06:06.680 he would be the best candidate for a 06:06.690 --> 06:09.400 for energy and match craft or a good energy match 06:09.400 --> 06:12.190 graft versus someone who is not a responder 06:12.190 --> 06:15.110 because there's certain individuals who 06:15.120 --> 06:17.720 feel that if someone is not one who 06:17.730 --> 06:20.080 forms antibody and if these antibodies are H. 06:20.080 --> 06:20.230 L. 06:20.230 --> 06:20.310 A. 06:20.310 --> 06:22.070 Specific which by definition of the H. 06:22.070 --> 06:22.250 L. 06:22.250 --> 06:22.480 A. 06:22.540 --> 06:23.700 Antigens they are. 06:23.710 --> 06:24.390 Because the H. 06:24.390 --> 06:24.550 L. 06:24.550 --> 06:24.650 A. 06:24.650 --> 06:27.360 Antigens have been defined by people's reactive 06:27.600 --> 06:29.340 reactivity to these antibodies. 06:29.450 --> 06:32.350 Therefore that knowing that someone's responder would then 06:32.360 --> 06:35.250 make him a candidate to wait for a better graft versus someone 06:35.250 --> 06:37.520 who isn't a responder should 06:37.530 --> 06:40.520 be transfused that transplanted at 06:40.520 --> 06:43.020 the first available organ that comes along and to 06:43.020 --> 06:45.120 disregard typing or H. 06:45.120 --> 06:45.260 L. 06:45.260 --> 06:45.330 A. 06:45.330 --> 06:46.960 Matching in these people. 06:47.870 --> 06:50.230 I don't think that this has been well 06:50.240 --> 06:52.520 established and agreed upon. 06:53.850 --> 06:56.580 I think there's arguments for both sides which I may be in a very 06:56.580 --> 06:59.510 confused way trying to present to you know I don't 06:59.510 --> 07:02.500 feel we should start transfusing people until there's convincing evidence 07:02.510 --> 07:05.470 that knowing whether someone forms antibody is 07:05.470 --> 07:06.380 worthwhile. 07:07.210 --> 07:07.510 Dr. 07:07.510 --> 07:08.120 Braun, 07:08.720 --> 07:10.140 What might be your opinion on this 1? 07:10.150 --> 07:11.150 I agree with you completely. 07:11.150 --> 07:13.750 I don't think it's approved at all that you can establish 07:15.380 --> 07:18.150 acceptable recipients by attempts to 07:18.160 --> 07:21.120 sensitize them in some unknown fashion and it's 07:21.120 --> 07:23.650 very uncertain as to 07:23.660 --> 07:26.300 whom you should sensitize with what sort of 07:26.300 --> 07:28.960 antigens in order to evoke this benevolent 07:28.960 --> 07:31.760 situation of acceptability of all kinds of 07:31.770 --> 07:32.250 graphs. 07:32.670 --> 07:35.670 And until we know that I think the greater likelihood is 07:35.670 --> 07:38.290 one of harm and risk to the patient of 07:38.290 --> 07:38.870 advantage. 07:41.040 --> 07:43.620 I think there's some evidence now that there's a way to 07:43.620 --> 07:46.530 compromise to find out what sort of delayed hypersensitivity 07:46.530 --> 07:48.600 response an individual has without using 07:49.040 --> 07:51.320 uh Lucas cider agent lee antigens. 07:51.690 --> 07:54.150 And I'm thinking of the work of mel Williams 07:54.150 --> 07:55.320 who did D. 07:55.320 --> 07:55.450 N. 07:55.450 --> 07:55.680 C. 07:55.680 --> 07:56.090 B. 07:56.380 --> 07:56.430 A. 07:56.430 --> 07:59.330 Coral Benzene delayed hypersensitivity testing 07:59.330 --> 08:02.260 on pre transplant patients who are on the waiting list. 08:02.640 --> 08:05.530 And if I remember his figures right he found that 08:05.780 --> 08:08.770 those individuals who gave a delayed hypersensitivity 08:08.770 --> 08:11.240 response to dynamic or Benzene, 08:11.560 --> 08:14.440 of them rejected their transplant for as the group 08:14.440 --> 08:16.470 that did not show a skin response. 08:16.470 --> 08:19.140 Only 27% rejected their transplant 08:20.630 --> 08:21.410 interestingly enough. 08:21.410 --> 08:24.160 He used only the cutaneous hypersensitivity 08:24.160 --> 08:24.860 method. 08:25.210 --> 08:27.780 Others have shown that if you look at the in vitro and in 08:27.780 --> 08:30.740 stimulation you can detect some individuals who really 08:30.740 --> 08:32.010 do have a response to D. 08:32.010 --> 08:32.130 N. 08:32.130 --> 08:32.300 C. 08:32.300 --> 08:32.450 B. 08:32.450 --> 08:34.230 That does not show up in the skin test. 08:34.660 --> 08:35.320 In other words, 08:35.640 --> 08:38.450 perhaps if he had looked at the in vitro response to the 08:38.460 --> 08:39.740 26% of the D. 08:39.740 --> 08:39.860 N. 08:39.860 --> 08:40.040 C. 08:40.040 --> 08:40.200 B. 08:40.200 --> 08:42.470 Negatives who rejected the skin grafts, 08:42.470 --> 08:45.330 you might have found that some of those actually were DNC responders who were 08:45.330 --> 08:46.430 not being identified. 08:47.130 --> 08:49.340 So no one knows what the 08:49.350 --> 08:52.150 actual molecular analogy is between D. 08:52.150 --> 08:52.260 N. 08:52.260 --> 08:52.450 C. 08:52.450 --> 08:52.620 B. 08:52.620 --> 08:53.010 And the H. 08:53.010 --> 08:53.170 L. 08:53.170 --> 08:53.250 A. 08:53.250 --> 08:54.040 Sensitization. 08:54.040 --> 08:56.980 But it seems to be an interesting phenomenon and several people 08:56.980 --> 08:57.660 have reported. 08:57.880 --> 09:00.860 So I guess the answer that I'm giving is that 09:01.170 --> 09:03.810 I think we should look into other antigen stimulation 09:03.810 --> 09:06.800 responses rather than a sensitization so that we can keep our 09:06.800 --> 09:09.470 options open for transplant and not develop 09:09.480 --> 09:11.660 hyper acute rejection. 09:13.010 --> 09:13.770 Do you have any comments? 09:14.400 --> 09:15.000 Yes. 09:15.000 --> 09:17.610 The same sort of situation holds in the 09:17.610 --> 09:20.280 studies of Coulson and Shumway 09:20.290 --> 09:22.260 who have shown that some patients 09:22.430 --> 09:24.680 are poor responders in 09:24.680 --> 09:25.470 Mlc. 09:25.480 --> 09:28.210 Probably based on some sort of circulating inhibitory 09:28.210 --> 09:31.140 substance in their serum and in fact this 09:31.140 --> 09:33.980 whole discussion really should be aimed at why 09:33.980 --> 09:36.030 an individual is not responding. 09:36.030 --> 09:38.400 Is it a genetically inherited ability to 09:38.400 --> 09:39.090 respond? 09:39.260 --> 09:41.920 Is it a acquired inhibitor of some 09:41.920 --> 09:42.500 sort? 09:42.570 --> 09:44.350 Is it a product of the disease? 09:44.350 --> 09:46.980 It could be related to the stage or of disease or the 09:46.980 --> 09:49.620 quality of the clinical 09:49.630 --> 09:51.950 treatment regimen for that patient. 09:52.080 --> 09:54.650 I think those things needed to find and I would agree with dr 09:54.650 --> 09:57.260 braun that willy nilly giving blood 09:57.260 --> 10:00.230 transfusions as a way to see whether or not someone will respond is an 10:00.230 --> 10:03.030 extremely risky way to measure this as yet 10:03.040 --> 10:05.050 very poorly understood phenomenon. 10:05.520 --> 10:07.760 I must say that in a study that we're doing 10:07.760 --> 10:10.580 with first with Dr Belser non with 10:10.580 --> 10:13.390 dr salvatore at the university of California in san Francisco 10:13.770 --> 10:14.850 were carefully analyzed. 10:14.900 --> 10:17.650 100 patients were actually studying and lymphocyte 10:17.650 --> 10:18.410 serum treatment. 10:18.750 --> 10:21.145 About 37 of those patients had pre for and 10:21.145 --> 10:24.025 antibodies obviously not to the cadaver donor 10:24.165 --> 10:26.855 because that would provide a positive cross match and would be 10:26.855 --> 10:29.815 excluded but 37% had antibodies against some other 10:29.815 --> 10:29.975 H. 10:29.975 --> 10:30.095 L. 10:30.095 --> 10:30.725 A antigens. 10:31.015 --> 10:33.615 And in that series we see no difference between those who 10:33.615 --> 10:36.245 had made antibodies and those that did not 10:38.250 --> 10:39.620 since you've brought that up. 10:40.470 --> 10:42.380 We have a question here for dr brian. 10:42.380 --> 10:45.050 And I'll have you comment out to Dr Dr brian, 10:45.050 --> 10:47.660 how do you rationalize the disparity and transplant results between 10:47.660 --> 10:49.590 institutions regarding preformed antibodies? 10:50.570 --> 10:51.230 Mhm. 10:53.500 --> 10:55.360 Well there's a whole list of 10:55.370 --> 10:56.970 things there, 10:56.970 --> 10:59.320 many of them technical um 11:00.000 --> 11:02.880 one that depends on a complete analysis of all 11:02.880 --> 11:05.760 available positive syrah from the recipient and this is 11:05.770 --> 11:08.090 getting to be a horrendous cataloging and 11:08.090 --> 11:10.880 library storage type of problem where 11:10.890 --> 11:13.730 sometimes in our patients who look presumptively 11:13.740 --> 11:15.500 negative on a cross match. 11:15.520 --> 11:18.480 We will have to haul out as many as 10 or 12 old 11:18.480 --> 11:21.030 syrah in order to actually confirm this many times, 11:21.030 --> 11:23.970 we found that patients who are being held on satellite programs 11:23.980 --> 11:24.730 elsewhere, 11:24.740 --> 11:27.510 who are being screened by another laboratory if they 11:27.510 --> 11:30.320 come to us without those serum specimens will have been 11:30.360 --> 11:33.070 shown to have spikes of antibody which would 11:33.160 --> 11:35.820 give positive reactions with prospective 11:35.830 --> 11:38.710 donors with which we were going to transplant 11:38.710 --> 11:40.520 them for a kidney. 11:40.960 --> 11:43.870 So it one is you must have available to 11:43.870 --> 11:46.720 you a tremendous library of syrah 11:46.720 --> 11:49.660 on any recipient on any potential recipient, 11:49.670 --> 11:50.490 cadaver waiting list. 11:50.490 --> 11:50.860 Secondly, 11:50.860 --> 11:53.690 you should do all your tests with delusions because 11:53.700 --> 11:56.690 undiluted there are some anti complementary factors that interfere. 11:56.700 --> 11:58.350 Uh thirdly, 11:58.360 --> 12:01.210 you should use some tests of increased sensitivity 12:01.220 --> 12:03.550 such as dr Lorton described. 12:04.000 --> 12:06.140 And dr deer avoid described with 12:06.150 --> 12:09.020 the detection of sensitization either by 12:09.020 --> 12:11.700 serological methods or by cellular defined 12:11.700 --> 12:12.170 methods. 12:12.180 --> 12:13.690 Uh fourth, 12:13.700 --> 12:16.610 there's also the possibility that in some individuals 12:16.620 --> 12:19.570 and we saw this happen on the table and reported it in 12:19.570 --> 12:21.520 transfusion a couple of years ago, 12:21.790 --> 12:24.790 patients who may have preformed antibody not directed 12:24.790 --> 12:27.520 against the kidney donor may have antibody 12:27.520 --> 12:30.300 reacted reacted against lymphocytes in the blood 12:30.300 --> 12:32.420 transfusion given at the time of transplant. 12:32.420 --> 12:35.370 And we saw a daughter hyper acutely reject her mother's 12:35.370 --> 12:36.030 kidney, 12:36.190 --> 12:38.970 even though the cross match against the mother was repeatedly 12:38.970 --> 12:41.640 negative before and after transplantation. 12:41.650 --> 12:44.230 But her white cell antibodies reacted 12:44.240 --> 12:47.180 with a unit of two of the 12:47.180 --> 12:50.090 three units of blood that she was given at the time 12:50.090 --> 12:50.750 of surgery. 12:50.760 --> 12:53.010 And because there was a hemorrhagic problem, 12:53.020 --> 12:55.790 one unit happened to be given as whole blood with 12:55.800 --> 12:58.650 abundant lymphocytes and she hyper acutely rejected 12:58.650 --> 12:59.500 on the table. 12:59.790 --> 13:02.440 Uh The only antibody that we could find 13:02.440 --> 13:05.110 reactive in this situation was the white cell 13:05.110 --> 13:07.280 antibody reactive against blood donors, 13:07.290 --> 13:08.350 not the kidney donor. 13:08.430 --> 13:10.170 This is another uncommon, 13:10.180 --> 13:12.810 rare but still uh remote 13:12.810 --> 13:13.600 possibility. 13:13.710 --> 13:16.420 The fifth reason I would say there's differences 13:16.420 --> 13:19.410 between reporting centers and this doesn't hold for the boston group because 13:19.410 --> 13:22.010 that's relatively a concise group. 13:22.280 --> 13:24.790 But in accumulation of data from 13:24.800 --> 13:26.820 uh by dr tara sake. 13:26.820 --> 13:29.710 He's relying on the heterogeneity of testing 13:29.710 --> 13:32.690 methodologies existing in probably 80 some 13:32.690 --> 13:33.440 laboratories, 13:33.910 --> 13:36.700 many of whom do or do not adhere to many of the 13:36.710 --> 13:38.450 criteria that we discussed this morning. 13:38.450 --> 13:40.460 And that makes for a very 13:41.290 --> 13:44.220 unstable type of reporting in my 13:44.220 --> 13:44.790 estimation, 13:45.500 --> 13:45.940 doctor. 13:45.940 --> 13:46.860 So you got any comments 13:52.880 --> 13:55.660 here's a question which is directed 13:55.670 --> 13:58.480 to no one in particular and that is what do 13:58.480 --> 14:01.120 biopsies look like And Group 14:01.120 --> 14:04.100 three or people who have excessive amounts of 14:04.100 --> 14:06.870 antibodies or strong responders as a 14:06.870 --> 14:09.210 cause of rejection is its cellular versus funeral. 14:09.950 --> 14:12.380 Uh I'm not aware of any published data that 14:12.390 --> 14:13.450 delineates this. 14:13.460 --> 14:16.410 It's been clearly shown that in individuals who 14:16.420 --> 14:18.560 have a chronic vascular 14:18.560 --> 14:21.280 rejection that this is humanly mediated, 14:21.280 --> 14:23.200 which was shown by the group of Emma at 14:23.210 --> 14:25.940 MGH we have seen 14:25.950 --> 14:28.730 individuals with high levels of antibody 14:28.740 --> 14:31.580 with both acute cellular as well as 14:31.580 --> 14:33.490 evidence for human rejection 14:33.500 --> 14:35.190 manifested as 14:35.200 --> 14:37.730 uh proliferation of their 14:37.730 --> 14:39.890 cells and uh 14:40.310 --> 14:43.100 also by 14:43.100 --> 14:43.760 immunosuppressants. 14:43.760 --> 14:46.740 We've seen immunoglobulins on the vessel walls which may 14:46.740 --> 14:49.020 or may not be uh significant. 14:49.390 --> 14:52.050 Clearly the ones who have hyper acute rejections. 14:52.050 --> 14:54.750 Its characteristic of a 14:55.410 --> 14:57.830 a policy cellular infiltrate of the interstitial man. 14:58.350 --> 15:01.000 Why would anyone else care to comment regarding that 15:01.000 --> 15:01.380 question? 15:03.660 --> 15:06.180 I'm not aware that these people classically 15:06.180 --> 15:09.070 have au Meral pathologic change 15:09.080 --> 15:11.510 or a cellular pathologic change. 15:15.300 --> 15:18.240 Uh There's a question here that's of interest which 15:18.240 --> 15:20.190 I'll throw up into any volunteer on the panel. 15:20.190 --> 15:23.170 What is the clinical significance of the two a.m. 15:23.170 --> 15:23.340 L. 15:23.340 --> 15:23.770 C. 15:23.770 --> 15:26.460 And the use of the recipient serum in the test system? 15:27.100 --> 15:27.580 Mhm. 15:28.660 --> 15:29.690 Any volunteers? 15:31.730 --> 15:34.530 The same study that we're undertaking with Belcher's group in SAn 15:34.530 --> 15:37.370 Francisco is the location of the first report of the 15:37.380 --> 15:38.970 significance of the two a.m. L. 15:38.970 --> 15:40.900 See that as we do at two a.m. L. 15:40.900 --> 15:41.110 C. 15:41.110 --> 15:44.110 In the macro system and you get a stimulation index of greater 15:44.110 --> 15:44.480 than eight. 15:44.490 --> 15:47.120 That is the response between the two is eight times 15:47.360 --> 15:50.220 the control responses that this 15:50.220 --> 15:52.130 correlates with rejection. 15:54.320 --> 15:56.900 This work was done I think about two years ago 15:57.290 --> 15:59.840 was considered highly significant and is highly 15:59.840 --> 16:02.560 significant when you look at it statistically data was 16:02.560 --> 16:05.020 reviewed carefully by Dr Van Rood who agreed with the 16:05.020 --> 16:07.940 significance in looking at the last 100 cases 16:07.940 --> 16:10.620 where we've been where our statisticians have been 16:10.620 --> 16:12.630 handling all of the data on the case including the M. 16:12.630 --> 16:12.760 L. 16:12.760 --> 16:12.990 C. 16:12.990 --> 16:13.180 S. 16:13.630 --> 16:15.910 You know the significance becomes less 16:15.920 --> 16:16.670 obvious. 16:18.360 --> 16:21.340 I'd like to comment that they had most of their 16:21.340 --> 16:21.610 data. 16:21.610 --> 16:24.520 That was uh that could be 16:24.520 --> 16:26.760 at least the stuff that was published two years ago. 16:26.880 --> 16:29.790 Most of the data was that was statistically significant 16:29.790 --> 16:32.780 and large enough numbers to calculate 16:32.790 --> 16:35.130 in a statistical way we're on the cadaver donors. 16:35.130 --> 16:37.560 And indeed it did show that uh they 16:37.560 --> 16:40.400 however uh in the living related had 16:40.400 --> 16:43.290 only three individuals who had a two way stimulation 16:43.290 --> 16:44.690 ratio greater than 1-8. 16:45.180 --> 16:47.900 And on the basis of this they felt that this was 16:47.900 --> 16:48.840 also significant. 16:49.560 --> 16:51.370 I I think that that's very weak. 16:51.380 --> 16:54.240 I personally would not refuse 16:54.240 --> 16:57.170 to do a living related transplants 16:57.180 --> 17:00.170 in individual that had a greater than one day 17:00.170 --> 17:02.260 stimulation on two a.m. L. 17:02.260 --> 17:02.790 C. 17:03.270 --> 17:06.130 Anyone else I'd just like to expand a little further 17:06.130 --> 17:06.360 to. 17:06.360 --> 17:08.350 And that is that the two a.m. L. 17:08.350 --> 17:08.510 C. 17:08.510 --> 17:08.600 S. 17:08.600 --> 17:11.250 That are being done are being done by a macro mlc system. 17:11.260 --> 17:13.730 It's interesting that we moved to a micro mlc system. 17:14.060 --> 17:16.680 This correlation apparently doesn't hold at all. 17:16.690 --> 17:18.070 Even in Kent Cochran's hands. 17:18.070 --> 17:20.950 The fellow who first reported this and also even at the 17:20.950 --> 17:23.510 time he first reported this when he tried to do one way ml 17:23.510 --> 17:26.470 CS both ways that didn't 17:26.470 --> 17:29.440 correlate making an extremely confusing picture. 17:29.440 --> 17:30.750 And so I would think that to M. 17:30.750 --> 17:30.910 L. 17:30.910 --> 17:31.590 C. 17:31.600 --> 17:34.450 Sees for decisions about transplantation should be 17:34.450 --> 17:36.960 one of those items to be held 17:36.960 --> 17:38.460 awaiting further evidence. 17:39.480 --> 17:40.910 Question for dr gary boy. 17:42.060 --> 17:43.130 We're in the experiments. 17:43.130 --> 17:46.020 You sided with the enhanced animals challenged with skin grafts at 17:46.030 --> 17:48.510 intervals following the successful kidney graft. 17:48.740 --> 17:50.810 And if not what would you predict would happen 17:52.090 --> 17:54.810 in the experiments that I showed this morning? 17:54.810 --> 17:56.420 These were passively enhanced animals. 17:56.430 --> 17:59.110 These animals were not subsequently challenge the skin 17:59.110 --> 17:59.520 graft. 17:59.670 --> 18:00.060 However, 18:00.060 --> 18:02.820 in animals who enhanced by the 18:02.820 --> 18:05.780 active process these animals became one 18:05.780 --> 18:07.750 and two year survivals survivors. 18:07.950 --> 18:10.690 Those animals did get skin grafts and those skin 18:10.690 --> 18:12.930 grafts were accepted very well. 18:16.190 --> 18:18.580 A question directed to me, 18:18.590 --> 18:21.490 the studies of the pelts and Tara sake have found that 18:21.490 --> 18:24.260 only about 50% of the transfused patients developed 18:24.270 --> 18:25.330 preformed antibodies. 18:25.330 --> 18:27.140 In contrast the data from Perkins. 18:27.150 --> 18:29.270 Uh I think that 18:29.930 --> 18:32.570 This is a variable percentage in 18:32.570 --> 18:35.530 various centers and it probably relates to the number of transfusions 18:35.530 --> 18:38.240 that people have had and uh 18:38.250 --> 18:40.640 the time in catching these individuals 18:40.640 --> 18:42.550 following their sensitization. 18:42.560 --> 18:45.140 Uh the ones who were greater than 18:45.140 --> 18:47.930 50% were numbers the 18:47.930 --> 18:50.810 85% figure where people would receive greater than 18:50.810 --> 18:52.440 20 transfusions on dialysis. 18:52.440 --> 18:55.010 Which is not a common practice 18:55.020 --> 18:57.740 in in my experience in talking with 18:57.740 --> 19:00.730 others so that I think the amount of 19:00.730 --> 19:03.710 exposure is going to determine the percentage of your population 19:03.720 --> 19:04.970 where you'll see this. 19:06.800 --> 19:09.720 There's another question which is directed to me and that is really Lucas pierce 19:09.720 --> 19:11.520 and Williams have incriminated subside. 19:11.520 --> 19:14.110 A toxic levels of antibody determined by 19:14.110 --> 19:16.520 standard tests as an important factor in graft 19:16.520 --> 19:17.170 rejection. 19:17.560 --> 19:20.560 Do you believe their results and should their techniques be incorporated in the 19:20.570 --> 19:22.130 pre transplant cross match? 19:22.530 --> 19:25.310 I myself am not familiar with the sub 19:25.310 --> 19:28.250 toxic levels of antibody determination that is being referred to 19:28.250 --> 19:29.910 as someone else here on the panel with. 19:30.450 --> 19:33.360 I don't know if they're referring to the immunity tests on kidney 19:33.360 --> 19:33.960 cells. 19:34.510 --> 19:37.220 Uh when Williams was working in hume's 19:37.220 --> 19:39.470 laboratory and the group down there was 19:39.470 --> 19:42.450 evaluating the sub toxic levels of 19:42.450 --> 19:42.970 antibody. 19:42.970 --> 19:45.950 They did show that by the immune adherence technique which was number five 19:45.950 --> 19:48.440 on dr bronze rating scale 19:48.560 --> 19:51.060 that you tested kidney 19:51.060 --> 19:53.770 cells from the donor with serum from 19:53.770 --> 19:54.710 the recipient. 19:54.720 --> 19:55.770 By this technique, 19:55.960 --> 19:58.510 they have apparently could pick up more sensitively 19:58.860 --> 20:01.790 the presence of antibodies than they could by lymphocytes 20:01.950 --> 20:02.400 toxicity. 20:02.410 --> 20:05.080 Which is not too surprising because lymphocytes 20:05.250 --> 20:07.780 toxicity is not a very sensitive 20:07.790 --> 20:08.360 assay. 20:08.640 --> 20:11.590 There are very few human serially diluted more than a couple of times. 20:11.590 --> 20:13.900 Will still kill human lymphocytes which is 20:13.900 --> 20:16.600 distinctly unlike any other side of toxicity 20:16.600 --> 20:18.170 system that I know of in biology. 20:18.290 --> 20:21.150 So that almost any other technique 20:21.270 --> 20:24.220 should be more sensitive in picking up these antibodies than the one that we're 20:24.220 --> 20:24.650 using 20:27.020 --> 20:27.540 enough. 20:27.550 --> 20:30.440 If the question is referring to the the 20:30.450 --> 20:33.280 late cross match and the 20:33.290 --> 20:33.560 L. 20:33.560 --> 20:36.240 G cross match and the 20:36.250 --> 20:38.520 anti g mediated cross 20:38.520 --> 20:40.330 match in my mind. 20:40.330 --> 20:42.440 There's no sufficient data to say that these 20:42.720 --> 20:44.890 uh techniques are 20:44.900 --> 20:47.430 are clinically significant as far as 20:47.440 --> 20:49.890 showing a greater or lesser survival 20:50.330 --> 20:53.050 in patients who have been transplanted with these being negative or 20:53.050 --> 20:53.770 positive. 20:54.270 --> 20:56.020 With the individual who asked this question. 20:56.020 --> 20:58.840 Care to comment on Zoltan Lucas has 20:58.840 --> 21:01.320 published on subliminal sensitization. 21:01.740 --> 21:04.600 Not detectable by standard sido toxicity but the 21:04.610 --> 21:06.990 detectable by more sophisticated techniques 21:07.310 --> 21:10.310 which employ variants of anti 21:10.310 --> 21:13.260 endothelial testing and that's what's really has 21:13.260 --> 21:13.520 done. 21:13.520 --> 21:16.480 And they've both shown uh people in the 21:16.480 --> 21:19.210 retrospective work primarily the 21:19.210 --> 21:21.210 reject ear's of their graphs. 21:21.220 --> 21:23.430 Uh The syrah from patients who have rejected 21:23.440 --> 21:24.450 transplants. 21:24.680 --> 21:27.300 Let's start over the pre transplant 21:27.300 --> 21:29.130 syrah examined 21:29.140 --> 21:31.900 retrospectively uh and 21:31.900 --> 21:34.820 patients who have rejected grass were found to be positive 21:34.830 --> 21:37.690 by these augmented side a toxic techniques or 21:37.690 --> 21:39.960 primarily by using a different target cell. 21:40.110 --> 21:42.470 Either kidney cell in the theater or something else. 21:42.590 --> 21:45.270 And that's what the question is really intended to 21:45.620 --> 21:46.560 get at. 21:46.710 --> 21:49.310 The problem with these techniques is preparation of the 21:49.310 --> 21:51.790 material or the length of the test 21:51.790 --> 21:52.420 required, 21:52.430 --> 21:55.360 which we're talking about 68 or 10 hours of 21:55.370 --> 21:58.250 cross match technique instead of three or four 21:58.270 --> 21:58.830 hours. 21:58.830 --> 22:00.700 As with the standard techniques for five hours. 22:00.700 --> 22:02.110 With standard techniques of course, 22:02.170 --> 22:03.420 Belser suggests, 22:03.430 --> 22:06.290 then explains that the fact that his 22:06.300 --> 22:09.130 patients do just as well who have antibody as 22:09.130 --> 22:10.030 those who don't. 22:10.150 --> 22:13.070 Is that his technique for cross matching is better And that's 22:13.070 --> 22:16.000 the framework from which the question was intended. 22:16.890 --> 22:19.720 The test you're referring to against what ophelia cells and 22:19.720 --> 22:20.380 kidney cells. 22:20.380 --> 22:22.290 Are these a sido toxic test 22:24.050 --> 22:25.300 uh, 22:25.310 --> 22:28.240 side of toxicity against kidney cells and then Williams published 22:28.240 --> 22:30.830 on immune adherence and Cirelli was 22:30.830 --> 22:33.380 against was anti endothelial antibody. 22:33.660 --> 22:35.740 I've forgotten what Lucas target cells. 22:36.520 --> 22:37.110 Yes, 22:37.110 --> 22:39.490 we've been looking at that using lymphocyte blasts 22:39.500 --> 22:42.230 with uh Peroni and 22:42.240 --> 22:45.130 scripts group and it is true you can pick up a toxic 22:45.130 --> 22:46.420 antibodies more sensitively. 22:46.630 --> 22:47.310 As I said before, 22:47.310 --> 22:50.280 I think you do it by almost any technique because the human lymphocyte is a 22:50.280 --> 22:51.420 very resistant cell. 22:51.700 --> 22:52.450 The question is, 22:52.460 --> 22:54.940 do they correlate with success? 22:54.950 --> 22:57.560 And that is a little harder to be sure of. 22:58.440 --> 23:01.350 I think all of these techniques should be used 23:01.360 --> 23:02.710 in a prospective study. 23:02.910 --> 23:05.750 We did a dr philo when he was in our 23:05.750 --> 23:07.560 laboratory before he went to University of Indiana, 23:07.560 --> 23:10.100 did a very nice study where he pre sensitized dogs 23:10.520 --> 23:13.360 and he found that even when he could detect sido toxic 23:13.360 --> 23:15.780 antibody at low levels there was no permanent 23:15.780 --> 23:17.770 rejection and no permanent loss of kidneys. 23:17.770 --> 23:20.430 It took a certain way level of antibody response 23:20.510 --> 23:22.720 in order to have permanent damage to kidneys. 23:22.730 --> 23:25.070 So that you would question just a little bit if 23:25.070 --> 23:28.040 the psycho toxic levels are so low that you can't detect them 23:28.040 --> 23:29.180 by our present techniques. 23:29.200 --> 23:31.660 Just how much significance is there, 23:31.660 --> 23:32.200 really? 23:32.560 --> 23:35.520 And when you look at the great variability and clinical 23:35.520 --> 23:36.000 results. 23:36.000 --> 23:38.980 It's very hard to correlate those kinds of data. 23:39.880 --> 23:42.780 I think you're getting at the question that I really wanted you to 23:42.780 --> 23:43.210 get at. 23:43.210 --> 23:44.120 And that's uh, 23:44.130 --> 23:46.780 is there are we talking about too sensitive 23:46.780 --> 23:49.510 techniques or false positive cross match is in a sense, 23:49.810 --> 23:51.970 in a sense of whether they're clinically significant. 23:51.980 --> 23:54.650 Because if you take it to continuing extremes, 23:54.650 --> 23:57.240 you will get to the point where no one can be transplanted 23:57.280 --> 23:59.800 because they have some kind of positive 23:59.800 --> 24:02.630 reaction to one of these ultra sensitive tests. 24:03.450 --> 24:04.780 I think that's a very valid point. 24:04.780 --> 24:05.000 I mean, 24:05.000 --> 24:07.890 what you're saying is ultimately we'll be doing nothing but identical 24:07.900 --> 24:08.380 twins. 24:09.180 --> 24:09.710 Yeah. 24:10.330 --> 24:11.230 Dr gary boy, 24:11.230 --> 24:13.560 your test of of self 24:13.560 --> 24:14.260 sensitivity 24:15.950 --> 24:18.800 Have received a great amount of 24:18.800 --> 24:19.630 enthusiasm. 24:19.640 --> 24:22.370 How do you feel as far as their significance in 24:23.450 --> 24:26.250 renal transplantation is concerned at the present time? 24:26.780 --> 24:26.990 Well, 24:26.990 --> 24:28.240 at the present time, 24:28.240 --> 24:29.320 I think it's still a two. 24:29.320 --> 24:30.590 It needs a lot of work. 24:30.720 --> 24:33.560 We really haven't done a large enough series of 24:33.570 --> 24:36.290 prospective patients to say what the clinical 24:36.290 --> 24:37.240 significance is. 24:37.300 --> 24:40.100 When we first did this series of tests up in 24:40.100 --> 24:41.020 Boston two years. 24:41.180 --> 24:44.040 So now we ask about 25 patients 24:44.040 --> 24:46.520 prior to transplantation at that time, 24:46.530 --> 24:49.240 five patients had a positive LPC 24:49.260 --> 24:51.010 reaction prior to transplantation. 24:51.020 --> 24:53.710 Three of them lost their kidney in the next two 24:53.710 --> 24:56.170 months was a very small number of patients to make 24:56.170 --> 24:58.570 any any conclusion of. 24:59.760 --> 25:01.790 And since I've been down here in San Antonio, 25:01.790 --> 25:03.980 we've also looked at another 20 five 25:03.990 --> 25:06.920 Patients and four or five of them again 25:06.920 --> 25:09.900 have also been positive and two or three of them 25:09.900 --> 25:12.650 have also lost a kidney in a very short period of time. 25:12.660 --> 25:15.390 But these survival results are 25:15.390 --> 25:17.580 indeed identical to the survival results. 25:17.580 --> 25:20.560 Most patients who did not have the positive prior 25:20.560 --> 25:21.730 to transplant. 25:22.040 --> 25:24.860 So I can't say that this group has a 25:24.860 --> 25:26.460 greater risk. 25:27.680 --> 25:29.880 I think it's of note that 25:30.880 --> 25:33.830 several instances now individuals who are 25:33.840 --> 25:34.050 H. 25:34.050 --> 25:34.200 L. 25:34.200 --> 25:35.930 A identical siblings who are M. 25:35.930 --> 25:36.080 L. 25:36.080 --> 25:36.310 C. 25:36.310 --> 25:38.580 Negative have been found to 25:38.580 --> 25:40.720 have sensitivity or pre 25:40.720 --> 25:42.470 sensitization to each other. 25:42.470 --> 25:45.070 And this has primarily been in patients with a plastic anemia who have 25:45.070 --> 25:47.660 received transfusions from H. 25:47.660 --> 25:47.790 L. 25:47.790 --> 25:47.880 A, 25:47.880 --> 25:48.770 identical sibs. 25:48.780 --> 25:51.370 But in these instances they've been able to find 25:51.840 --> 25:54.830 that they can develop a positive 25:54.840 --> 25:57.600 LMC or cell mediated side uh license 25:57.600 --> 25:59.580 test as well as an antibody 25:59.800 --> 26:02.420 induced cell cell mediated psycho 26:02.420 --> 26:03.300 toxicity. 26:03.310 --> 26:06.150 And this would imply therefore that 26:06.160 --> 26:08.230 the sensitizing 26:08.240 --> 26:10.880 uh an agent or agent 26:10.890 --> 26:13.300 or inheritance of the sensitizing agent 26:13.310 --> 26:16.050 is one which is not uh 26:16.060 --> 26:18.720 inherited on the chromosome or a 26:18.720 --> 26:19.990 wheel of the H. 26:19.990 --> 26:20.170 L. 26:20.170 --> 26:20.500 A. 26:20.510 --> 26:21.240 System. 26:21.720 --> 26:23.900 And since the renal survival and H. 26:23.900 --> 26:24.040 L. 26:24.040 --> 26:25.720 A identical sibs is 26:26.820 --> 26:29.790 pretty uniform throughout the world as being certainly greater 26:29.790 --> 26:30.660 than 90%. 26:30.670 --> 26:32.420 And excluding technical failures, 26:32.750 --> 26:35.510 certainly greater than 95% would 26:35.510 --> 26:37.910 imply that at least in certain instances pre 26:37.910 --> 26:40.430 sensitization is detected by the L. 26:40.430 --> 26:40.560 M. 26:40.560 --> 26:40.750 C. 26:40.750 --> 26:41.180 Or the A. 26:41.180 --> 26:41.260 I. 26:41.260 --> 26:41.440 L. 26:41.440 --> 26:41.560 M. 26:41.560 --> 26:42.020 C. 26:42.100 --> 26:43.080 R. 26:43.090 --> 26:43.850 R. 26:43.860 --> 26:46.600 Sensations that are perhaps not significant with 26:46.600 --> 26:48.490 regards to kidney transplant. 26:48.710 --> 26:51.600 They may well indeed however have a great significance in 26:51.600 --> 26:52.610 bell marrow transplants. 26:52.610 --> 26:54.690 And I'll ask dr sell his comments on that. 26:56.400 --> 26:56.620 Well. 26:56.620 --> 26:59.500 We have only done about 11 or 12 bone marrow 26:59.500 --> 27:02.430 transplants and we've looked for these reactions in those 27:02.430 --> 27:05.020 patients and in our identical 27:05.640 --> 27:07.910 matched but non identical, 27:07.920 --> 27:09.040 otherwise not identical. 27:09.040 --> 27:11.990 Sibs we've not seen these kinds of reactions 27:12.150 --> 27:14.990 but I've been very intrigued by a recent as yet 27:15.000 --> 27:17.870 unpublished report from Bruce comida which 27:17.870 --> 27:20.230 showed that there are killer 27:20.240 --> 27:22.930 lymphocytes present in the marrow of 27:22.930 --> 27:25.890 sibs directed against other sibs in 27:25.890 --> 27:28.880 the family without pre sensitization and being 27:28.880 --> 27:31.800 genetically inherited apparently 27:31.810 --> 27:34.690 through chromosomes other than those that handle the 27:34.690 --> 27:35.800 mlc locus. 27:35.850 --> 27:38.730 And uh this kind of 27:38.740 --> 27:41.440 genetically occurring spontaneously occurring 27:41.450 --> 27:44.120 CML reaction may well have 27:44.130 --> 27:47.050 tremendous significance in the bone marrow 27:47.060 --> 27:48.720 transplant situation. 27:48.810 --> 27:51.660 We've only recently learned of this and now we 27:51.660 --> 27:52.910 and others thomas. 27:52.920 --> 27:54.970 I think everyone is now looking for those reactions 27:55.350 --> 27:58.230 because they may be extremely important in 27:58.230 --> 27:58.950 graft survival. 27:58.950 --> 27:59.620 As you know, 27:59.630 --> 28:02.260 fully 25% of a 28:02.260 --> 28:05.180 plastic anemic patients will reject their graphs 28:05.640 --> 28:08.300 despite the fact that they're mlc negative and 28:08.310 --> 28:09.710 perfectly identical at the H. 28:09.710 --> 28:09.840 L. 28:09.840 --> 28:09.910 A. 28:09.910 --> 28:10.290 Locust. 28:10.290 --> 28:12.270 25% will reject their graphs. 28:15.920 --> 28:18.460 Hist o compatibility testing 28:19.360 --> 28:22.170 a panel discussion with dr braun, 28:22.690 --> 28:25.660 doctor Cell Dr Gary boy 28:26.270 --> 28:27.700 and Dr species 28:30.850 --> 28:33.310 was moderated by Roberti Lord in 28:33.410 --> 28:34.410 Lieutenant Colonel U. 28:34.410 --> 28:34.580 S. 28:34.580 --> 28:35.310 Air Force M. 28:35.310 --> 28:35.840 C. 28:35.870 --> 28:37.940 Assistant Chief reno service. 28:37.950 --> 28:38.790 Wilford Hall U. 28:38.790 --> 28:38.960 S. 28:38.960 --> 28:40.350 Air Force Medical Center, 28:40.580 --> 28:43.560 Lackland Air Force Base and produced 28:43.560 --> 28:46.070 through the mobile facilities of the television division, 28:46.330 --> 28:47.840 Academy of Health Sciences, 28:47.840 --> 28:49.050 United States Army, 28:49.300 --> 28:51.040 Fort SAm Houston texas.